Cell insight最新文献

英文中文

Fight Alzheimer's disease with cancer 用癌症对抗阿尔茨海默病

Cell insight

Pub Date : 2026-01-24 DOI: 10.1016/j.cellin.2026.100300

Tongmei Zhang , Weihong Song

引用次数: 0

An additional site mutation in MITA/STING gain-of-function mutants abolishes the autoimmune SAVI phenotypes and directs a therapeutic strategy MITA/STING功能获得突变体中的另一个位点突变可消除自身免疫性SAVI表型并指导治疗策略

Cell insight

Pub Date : 2026-01-07 DOI: 10.1016/j.cellin.2026.100298

Fang-Xu Li , Sheng Liu , Zhi-Dong Zhang , Xin Shuai , Bi-Kun Xiao , Jia Yang , Defen Lu , Dandan Lin , Guijun Shang , Bo Zhong

STING-associated vasculopathy with onset in infancy (SAVI) is an autoimmune disease caused by gain-of-function mutations (GOFs) of MITA/STING and the most frequent GOFs for SAVI are MITA^N154S and MITA^V155M. However, how MITA GOFs are spontaneously activated remains incompletely understood. Here, we show that the activity of MITA hinge-region GOFs is compromised by an additional mutation at Lys150 and that the SAVI phenotypes of MITA^N153S/WT mice are completely abolished in the MITA^K150N/N153S (MITA^NS/NS) mice. Mechanistically, MITA GOFs constitutively associate with iRhom2 for the spontaneous ER-to-Golgi translocation, which is substantially inhibited by the introduction of a mutation at Lys150. Interestingly, cGAMP binds to MITA^NS, triggers the ER-to-Golgi translocation of MITA^NS as well as the MITA^NS-iRhom2 interaction, and induces the expression of downstream genes in Mita^NS/NS cells similarly as in Mita^+/+ cells. Consistently, structural studies demonstrate an inactive open conformation of apo-MITA^NS characterized by connector region crossover and a curved filament of cGAMP-bound MITA^NS characterized by parallel connector regions, similar to those observed in wild-type MITA. Furthermore, we design a SAVI-inhibitory peptide (SIP) that selectively inhibits the interaction between hMITA^N154S (mMITA^N153S) and iRhom2 and the activity of MITA GOFs and thereby abolishes the SAVI phenotypes of the MITA^N153S/WT→WT chimeric mice. These findings reveal a previously uncharacterized mechanism for the spontaneous activation of MITA GOFs and highlight a potential therapeutic intervention for SAVI.

婴儿期起病的STING相关血管病变（SAVI）是由MITA/STING的功能获得性突变（GOFs）引起的自身免疫性疾病，SAVI最常见的GOFs是MITAN154S和MITAV155M。然而，MITA GOFs是如何自发激活的仍不完全清楚。在这里，我们发现MITA铰链区GOFs的活性受到Lys150处额外突变的损害，并且MITAN153S/WT小鼠的SAVI表型在MITAK150N/N153S （MITANS/NS）小鼠中完全被消除。从机制上讲，MITA GOFs与iRhom2组成性地结合，用于自发的ER-to-Golgi易位，该易位通过在Lys150处引入突变而被实质性地抑制。有趣的是，cGAMP与MITANS结合，触发MITANS的ER-to-Golgi易位以及MITANS- irhom2相互作用，并诱导MITANS /NS细胞中下游基因的表达，类似于Mita+/+细胞。与此一致的是，结构研究表明，apo-MITANS具有非活性的开放构象，其特征是连接器区域交叉，cgamp结合的MITANS具有弯曲的丝，其特征是平行的连接器区域，与野生型MITA相似。此外，我们设计了一种SAVI抑制肽（SIP），选择性抑制hMITAN154S （mMITAN153S）和iRhom2之间的相互作用以及MITA GOFs的活性，从而消除MITAN153S/WT→WT嵌合小鼠的SAVI表型。这些发现揭示了MITA GOFs自发激活的先前未被描述的机制，并强调了SAVI的潜在治疗干预。

{"title":"An additional site mutation in MITA/STING gain-of-function mutants abolishes the autoimmune SAVI phenotypes and directs a therapeutic strategy","authors":"Fang-Xu Li , Sheng Liu , Zhi-Dong Zhang , Xin Shuai , Bi-Kun Xiao , Jia Yang , Defen Lu , Dandan Lin , Guijun Shang , Bo Zhong","doi":"10.1016/j.cellin.2026.100298","DOIUrl":"10.1016/j.cellin.2026.100298","url":null,"abstract":"<div><div>STING-associated vasculopathy with onset in infancy (SAVI) is an autoimmune disease caused by gain-of-function mutations (GOFs) of MITA/STING and the most frequent GOFs for SAVI are MITA<sup>N154S</sup> and MITA<sup>V155M</sup>. However, how MITA GOFs are spontaneously activated remains incompletely understood. Here, we show that the activity of MITA hinge-region GOFs is compromised by an additional mutation at Lys150 and that the SAVI phenotypes of MITA<sup>N153S/WT</sup> mice are completely abolished in the MITA<sup>K150N/N153S</sup> (MITA<sup>NS/NS</sup>) mice. Mechanistically, MITA GOFs constitutively associate with iRhom2 for the spontaneous ER-to-Golgi translocation, which is substantially inhibited by the introduction of a mutation at Lys150. Interestingly, cGAMP binds to MITA<sup>NS</sup>, triggers the ER-to-Golgi translocation of MITA<sup>NS</sup> as well as the MITA<sup>NS</sup>-iRhom2 interaction, and induces the expression of downstream genes in <em>Mita</em><sup>NS/NS</sup> cells similarly as in <em>Mita</em><sup>+/+</sup> cells. Consistently, structural studies demonstrate an inactive open conformation of apo-MITA<sup>NS</sup> characterized by connector region crossover and a curved filament of cGAMP-bound MITA<sup>NS</sup> characterized by parallel connector regions, similar to those observed in wild-type MITA. Furthermore, we design a SAVI-inhibitory peptide (SIP) that selectively inhibits the interaction between hMITA<sup>N154S</sup> (mMITA<sup>N153S</sup>) and iRhom2 and the activity of MITA GOFs and thereby abolishes the SAVI phenotypes of the MITA<sup>N153S/WT</sup>→WT chimeric mice. These findings reveal a previously uncharacterized mechanism for the spontaneous activation of MITA GOFs and highlight a potential therapeutic intervention for SAVI.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"5 1","pages":"Article 100298"},"PeriodicalIF":0.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Host-pathogen interactions in African swine fever: From viral entry to systemic disease progression 非洲猪瘟的宿主-病原体相互作用：从病毒进入到全身性疾病进展

Cell insight

Pub Date : 2025-12-26 DOI: 10.1016/j.cellin.2025.100297

Danyang Zhang , Shilei Zhang , Fayu Yang , Zixiang Zhu , Haixue Zheng

African swine fever virus (ASFV), a large and complex double-stranded DNA virus, is the etiological agent of African swine fever (ASF). ASF is a highly contagious and lethal hemorrhagic disease in domestic swine, which poses a persistent threat to global swine production and food security. Despite extensive research efforts, the development of safe and effective vaccines or antivirals remains elusive. This is largely attributable to the incomplete understanding of the intricate replication cycle of ASFV and its multifaceted evasion of host defenses. The mechanisms by which ASFV orchestrates widespread damage within the host to maintain its highly efficient replication and evade host defenses remain a key question in the field. In this comprehensive review, we aim to synthesize the current understanding of the key mechanisms underlying ASFV replication and immune evasion, as well as the associated host damage. By integrating these insights with the clinical and pathological features of ASF, we seek to deepen our comprehension of the viral pathogenic mechanisms and highlight existing research gaps. Ultimately, our goal is to provide valuable guidance for future endeavors in vaccine and antiviral drug development.

非洲猪瘟病毒（African swine fever virus， ASFV）是非洲猪瘟（African swine fever， ASF）的病原，是一种大型、复杂的双链DNA病毒。非洲猪瘟是一种在家猪中具有高度传染性和致死性的出血性疾病，对全球养猪生产和粮食安全构成持续威胁。尽管进行了广泛的研究工作，但开发安全有效的疫苗或抗病毒药物仍然难以捉摸。这在很大程度上归因于对ASFV复杂的复制周期及其对宿主防御的多方面逃避的不完全理解。ASFV在宿主内协调广泛破坏以维持其高效复制和逃避宿主防御的机制仍然是该领域的关键问题。在这篇全面的综述中，我们旨在综合目前对ASFV复制和免疫逃避的关键机制以及相关的宿主损伤的理解。通过将这些见解与非洲猪瘟的临床和病理特征相结合，我们寻求加深对病毒致病机制的理解，并突出现有的研究空白。最终，我们的目标是为未来疫苗和抗病毒药物的开发提供有价值的指导。

{"title":"Host-pathogen interactions in African swine fever: From viral entry to systemic disease progression","authors":"Danyang Zhang , Shilei Zhang , Fayu Yang , Zixiang Zhu , Haixue Zheng","doi":"10.1016/j.cellin.2025.100297","DOIUrl":"10.1016/j.cellin.2025.100297","url":null,"abstract":"<div><div>African swine fever virus (ASFV), a large and complex double-stranded DNA virus, is the etiological agent of African swine fever (ASF). ASF is a highly contagious and lethal hemorrhagic disease in domestic swine, which poses a persistent threat to global swine production and food security. Despite extensive research efforts, the development of safe and effective vaccines or antivirals remains elusive. This is largely attributable to the incomplete understanding of the intricate replication cycle of ASFV and its multifaceted evasion of host defenses. The mechanisms by which ASFV orchestrates widespread damage within the host to maintain its highly efficient replication and evade host defenses remain a key question in the field. In this comprehensive review, we aim to synthesize the current understanding of the key mechanisms underlying ASFV replication and immune evasion, as well as the associated host damage. By integrating these insights with the clinical and pathological features of ASF, we seek to deepen our comprehension of the viral pathogenic mechanisms and highlight existing research gaps. Ultimately, our goal is to provide valuable guidance for future endeavors in vaccine and antiviral drug development.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"5 1","pages":"Article 100297"},"PeriodicalIF":0.0,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to “The role of TRPV4 in acute sleep deprivation-induced memory impairment: Mechanisms of calcium dysregulation and synaptic plasticity disruption.” [Cell Insight 4 (2025) 100240] “TRPV4在急性睡眠剥夺引起的记忆障碍中的作用：钙调节失调和突触可塑性破坏的机制”的勘误。[Cell Insight 4 (2025) 100240]

Cell insight

Pub Date : 2025-12-24 DOI: 10.1016/j.cellin.2025.100296

Meimei Guo , Feiyang Zhang , Sha Liu , Yi Zhang , Lesheng Wang , Jian Song , Wei Wei , Xiang Li

引用次数: 0

Hydrophobic tagging: A promising paradigm for targeted protein degradation 疏水标签：靶向蛋白降解的一个有前途的范例

Cell insight

Pub Date : 2025-12-04 DOI: 10.1016/j.cellin.2025.100295

Lilan Xin , Hongli Wang , Maoze Yang , Zhangxiao Guo , Man Zhu , Terry W. Moore , Chune Dong , Hai-Bing Zhou

Targeted protein degradation (TPD) has emerged as a groundbreaking therapeutic strategy, overcoming the limitations of traditional occupancy-driven pharmacology. Among TPD strategies, hydrophobic tag (HyT) technology exemplifies this paradigm shift by hijacking cellular protein quality control mechanisms for precise protein elimination. Structurally, HyT molecules integrate a target-specific ligand with a hydrophobic domain that emulates misfolded protein surfaces, facilitating selective recruitment of chaperone systems (e.g., heat shock protein 70, HSP70) and ubiquitin-proteasome system (UPS) activation, circumventing the E3 ligase dependency inherent to proteolysis-targeting chimera (PROTAC) systems. This innovative strategy offers distinct therapeutic benefits, including enhanced tissue-specific accumulation and the capacity to overcome resistance mechanisms. This review highlights the important advances in this rapidly growing field and critical limitations encountered in developing HyT degraders by analyzing the current status and representative examples of HyTs in degrading diverse pathogenic proteins, including oncogenic drivers (e.g., signal transducer and activator of transcription 3, STAT3), neurodegenerative aggregates (tau, α-synuclein), and viral envelope proteins. The critical developments, including the rational design of hydrophobic motifs and possible mechanistic insight into the degradation process of HyTs, have also been discussed.

靶向蛋白降解（TPD）已经成为一种突破性的治疗策略，克服了传统占位驱动药理学的局限性。在TPD策略中，疏水标签（HyT）技术通过劫持细胞蛋白质质量控制机制来精确消除蛋白质，体现了这种范式转变。在结构上，HyT分子将靶特异性配体与疏水结构域整合在一起，模拟错误折叠的蛋白质表面，促进伴侣系统（例如，热休克蛋白70，HSP70）的选择性招募和泛素-蛋白酶体系统（UPS）的激活，绕过了蛋白水解靶向嵌合体（PROTAC）系统固有的E3连接酶依赖性。这种创新策略提供了独特的治疗益处，包括增强组织特异性积累和克服耐药机制的能力。本文通过分析HyT降解多种致病蛋白的现状和代表性例子，包括致癌驱动因子（如转录信号换能器和激活因子3，STAT3），神经退行性聚集体（tau， α-突触核蛋白）和病毒包膜蛋白，强调了这一快速发展领域的重要进展和开发HyT降解物所遇到的关键限制。关键的发展，包括合理的设计疏水基序和可能的机制洞察到HyTs的降解过程，也进行了讨论。

{"title":"Hydrophobic tagging: A promising paradigm for targeted protein degradation","authors":"Lilan Xin , Hongli Wang , Maoze Yang , Zhangxiao Guo , Man Zhu , Terry W. Moore , Chune Dong , Hai-Bing Zhou","doi":"10.1016/j.cellin.2025.100295","DOIUrl":"10.1016/j.cellin.2025.100295","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) has emerged as a groundbreaking therapeutic strategy, overcoming the limitations of traditional occupancy-driven pharmacology. Among TPD strategies, hydrophobic tag (HyT) technology exemplifies this paradigm shift by hijacking cellular protein quality control mechanisms for precise protein elimination. Structurally, HyT molecules integrate a target-specific ligand with a hydrophobic domain that emulates misfolded protein surfaces, facilitating selective recruitment of chaperone systems (e.g., heat shock protein 70, HSP70) and ubiquitin-proteasome system (UPS) activation, circumventing the E3 ligase dependency inherent to proteolysis-targeting chimera (PROTAC) systems. This innovative strategy offers distinct therapeutic benefits, including enhanced tissue-specific accumulation and the capacity to overcome resistance mechanisms. This review highlights the important advances in this rapidly growing field and critical limitations encountered in developing HyT degraders by analyzing the current status and representative examples of HyTs in degrading diverse pathogenic proteins, including oncogenic drivers (e.g., signal transducer and activator of transcription 3, STAT3), neurodegenerative aggregates (tau, α-synuclein), and viral envelope proteins. The critical developments, including the rational design of hydrophobic motifs and possible mechanistic insight into the degradation process of HyTs, have also been discussed.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"5 1","pages":"Article 100295"},"PeriodicalIF":0.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HTATSF1 regulates innate antiviral immune response by orchestrating TRAF3-IRF3 and TRAF6-NF-κB pathways HTATSF1通过协调TRAF3-IRF3和TRAF6-NF-κB通路调控先天抗病毒免疫反应

Cell insight

Pub Date : 2025-11-26 DOI: 10.1016/j.cellin.2025.100294

Jia-Qing Zeng, Zi-Lun Ruan, Qi Zhang, Xue-Mei Yi, Yun-Da Chen, Ming-Ming Hu, Shu Li

Upon infection, viral DNA/RNA is detected by cGAS/RIG-I-like receptors, triggering the adaptor MITA/STING- or VISA/MAVS-dependent innate antiviral immune response respectively. Both adaptors recruit the conserved TRAF3 and TRAF6 to activate TBK1-IRF3 and TAK1-NF-κB pathways respectively, leading to collaborative induction of antiviral effector genes. How the functions of TRAF3 and TRAF6 bifurcate in innate antiviral signaling remains enigmatic. We identified HTATSF1 as a positive regulator of virus-triggered innate antiviral response. Upon viral infection, HTATSF1 promotes HECTD3-catalyzed K63-linked polyubiquitination of TRAF3, leading to its recruitment of TBK1 and activation of IRF3. In contrast, HTATSF1 promotes recruitment of TAK1 to TRAF6 and activation of the TAK1-IKK-NF-κB axis independently of HECTD3. HTATSF1-deficiency impairs induction of downstream antiviral genes, and HTATSF1-deficient mice exhibit decreased cytokine production and increased mortality upon viral infection. Our findings demonstrate that HTATSF1 is an essential regulator of innate antiviral immune response by orchestrating the TRAF3-IRF3 and TRAF6-NF-κB pathways.

感染后，病毒DNA/RNA被cGAS/ rig - i样受体检测，分别触发适配器MITA/STING或VISA/ mavs依赖性先天抗病毒免疫反应。这两个接头分别招募保守的TRAF3和TRAF6激活TBK1-IRF3和TAK1-NF-κB通路，从而协同诱导抗病毒效应基因。TRAF3和TRAF6的功能如何在先天抗病毒信号传导中分化仍然是一个谜。我们发现HTATSF1是病毒触发的先天抗病毒反应的正调节因子。在病毒感染后，HTATSF1促进了hector 3催化的K63-linked TRAF3的多泛素化，导致其招募TBK1和激活IRF3。相反，HTATSF1独立于hector 3促进TAK1向TRAF6的募集和TAK1- ikk - nf -κB轴的激活。htatsf1缺陷损害下游抗病毒基因的诱导，htatsf1缺陷小鼠在病毒感染后表现出细胞因子产生减少和死亡率增加。我们的研究结果表明，HTATSF1通过协调TRAF3-IRF3和TRAF6-NF-κB通路，是先天抗病毒免疫反应的重要调节因子。

{"title":"HTATSF1 regulates innate antiviral immune response by orchestrating TRAF3-IRF3 and TRAF6-NF-κB pathways","authors":"Jia-Qing Zeng, Zi-Lun Ruan, Qi Zhang, Xue-Mei Yi, Yun-Da Chen, Ming-Ming Hu, Shu Li","doi":"10.1016/j.cellin.2025.100294","DOIUrl":"10.1016/j.cellin.2025.100294","url":null,"abstract":"<div><div>Upon infection, viral DNA/RNA is detected by cGAS/RIG-I-like receptors, triggering the adaptor MITA/STING- or VISA/MAVS-dependent innate antiviral immune response respectively. Both adaptors recruit the conserved TRAF3 and TRAF6 to activate TBK1-IRF3 and TAK1-NF-κB pathways respectively, leading to collaborative induction of antiviral effector genes. How the functions of TRAF3 and TRAF6 bifurcate in innate antiviral signaling remains enigmatic. We identified HTATSF1 as a positive regulator of virus-triggered innate antiviral response. Upon viral infection, HTATSF1 promotes HECTD3-catalyzed K63-linked polyubiquitination of TRAF3, leading to its recruitment of TBK1 and activation of IRF3. In contrast, HTATSF1 promotes recruitment of TAK1 to TRAF6 and activation of the TAK1-IKK-NF-κB axis independently of HECTD3. HTATSF1-deficiency impairs induction of downstream antiviral genes, and HTATSF1-deficient mice exhibit decreased cytokine production and increased mortality upon viral infection. Our findings demonstrate that HTATSF1 is an essential regulator of innate antiviral immune response by orchestrating the TRAF3-IRF3 and TRAF6-NF-κB pathways.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"5 1","pages":"Article 100294"},"PeriodicalIF":0.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cover 封面

Cell insight

Pub Date : 2025-11-19 DOI: 10.1016/S2772-8927(25)00062-8

引用次数: 0

CXCL4 and CXCL4L1 activate human macrophage via TLR4 signaling to modulate inflammatory responses CXCL4和CXCL4L1通过TLR4信号激活人巨噬细胞，调节炎症反应

Cell insight

Pub Date : 2025-11-06 DOI: 10.1016/j.cellin.2025.100287

Han Bai , Ruoxi Yuan , Dong Yan , Liyuan Liang , Ru Zhang , Yao Xu , Zeqiong Cai , Doudou Ren , Yueyang Chong , Kexin Wang , Rongfu Tu , Miao Li , Xiao Zhao , Yanan Wang , Yurong Chen , Ying Cui , Yaguang Zhang , Chao Yang

The chemokine CXCL4 activates human monocytes/macrophages and contributes to the pathogenesis of inflammatory and fibrotic diseases. However, the receptor of CXCL4, CXCR3, is not expressed in human monocytes/macrophages. Thus, signaling pathways and receptors that mediate human monocytes/macrophages response to CXCL4 alone are not well characterized. Using human primary monocytes and mouse bone marrow-derived macrophages, we reported that CXCL4 activated NF-κB and a TBK1-JNK-AP1 signaling axis that drove the expression of inflammatory, fibrotic and neutrophil chemokine genes, and also a TRIF-RIPK3 axis-dependent necroptosis in primary human monocytes. Surprisingly, multiple evidence targeting TLR4 expression and function suggested a role for TLR4 in CXCL4 responses. Further, we show that CXCL4 and its natural variant CXCL4L1 interact with TLR4/MD-2 complex in human monocytes and CXCL4L1 induced a transcriptomic profile divergent to LPS. Ectopic expression of human CXCL4L1 using adeno-associated virus (AAV) system effectively mitigated papain-induced asthma in wild-type (WT) mice. Notably, the therapeutic impact of CXCL4L1 was absent in Tlr4^−/− mice. Our findings indicate that CXCL4 and its variant CXCL4L1 modulate inflammatory and fibrotic gene expression, as well as necroptosis in human monocytes, and regulating lung inflammation through TLR4-dependent signaling, highlighting TLR4's critical role in the pathophysiological response to CXCL4/CXCL4L1.

趋化因子CXCL4激活人单核/巨噬细胞，参与炎症和纤维化疾病的发病机制。然而，CXCL4的受体CXCR3在人单核细胞/巨噬细胞中不表达。因此，介导人单核/巨噬细胞对CXCL4反应的信号通路和受体尚未得到很好的表征。利用人原代单核细胞和小鼠骨髓源性巨噬细胞，我们报道了CXCL4激活NF-κB和TBK1-JNK-AP1信号轴，这些信号轴驱动炎症、纤维化和中性粒细胞趋化因子基因的表达，以及TRIF-RIPK3轴依赖性的人原代单核细胞坏死。令人惊讶的是，针对TLR4表达和功能的多个证据表明TLR4在CXCL4应答中发挥作用。此外，我们发现CXCL4及其天然变体CXCL4L1与人单核细胞中的TLR4/MD-2复合物相互作用，并且CXCL4L1诱导了与LPS不同的转录组谱。利用腺相关病毒（AAV）系统异位表达人CXCL4L1可有效减轻木瓜蛋白酶诱导的野生型（WT）小鼠哮喘。值得注意的是，CXCL4L1在Tlr4−/−小鼠中没有治疗作用。我们的研究结果表明，CXCL4及其变体CXCL4L1调节人类单核细胞的炎症和纤维化基因表达以及坏死坏死，并通过TLR4依赖的信号传导调节肺部炎症，突出了TLR4在CXCL4/CXCL4L1的病理生理反应中的关键作用。

{"title":"CXCL4 and CXCL4L1 activate human macrophage via TLR4 signaling to modulate inflammatory responses","authors":"Han Bai , Ruoxi Yuan , Dong Yan , Liyuan Liang , Ru Zhang , Yao Xu , Zeqiong Cai , Doudou Ren , Yueyang Chong , Kexin Wang , Rongfu Tu , Miao Li , Xiao Zhao , Yanan Wang , Yurong Chen , Ying Cui , Yaguang Zhang , Chao Yang","doi":"10.1016/j.cellin.2025.100287","DOIUrl":"10.1016/j.cellin.2025.100287","url":null,"abstract":"<div><div>The chemokine CXCL4 activates human monocytes/macrophages and contributes to the pathogenesis of inflammatory and fibrotic diseases. However, the receptor of CXCL4, CXCR3, is not expressed in human monocytes/macrophages. Thus, signaling pathways and receptors that mediate human monocytes/macrophages response to CXCL4 alone are not well characterized. Using human primary monocytes and mouse bone marrow-derived macrophages, we reported that CXCL4 activated NF-κB and a TBK1-JNK-AP1 signaling axis that drove the expression of inflammatory, fibrotic and neutrophil chemokine genes, and also a TRIF-RIPK3 axis-dependent necroptosis in primary human monocytes. Surprisingly, multiple evidence targeting TLR4 expression and function suggested a role for TLR4 in CXCL4 responses. Further, we show that CXCL4 and its natural variant CXCL4L1 interact with TLR4/MD-2 complex in human monocytes and CXCL4L1 induced a transcriptomic profile divergent to LPS. Ectopic expression of human CXCL4L1 using adeno-associated virus (AAV) system effectively mitigated papain-induced asthma in wild-type (WT) mice. Notably, the therapeutic impact of CXCL4L1 was absent in <em>Tlr4</em><sup>−/−</sup> mice. Our findings indicate that CXCL4 and its variant CXCL4L1 modulate inflammatory and fibrotic gene expression, as well as necroptosis in human monocytes, and regulating lung inflammation through TLR4-dependent signaling, highlighting TLR4's critical role in the pathophysiological response to CXCL4/CXCL4L1.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"5 1","pages":"Article 100287"},"PeriodicalIF":0.0,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Loop engineering of AtCas9 for effective and broad genome editing AtCas9环工程用于有效和广泛的基因组编辑

Cell insight

Pub Date : 2025-10-22 DOI: 10.1016/j.cellin.2025.100286

Yue-Lin Zhang , Dong-Chao Huang , Min Duan , Yu-Ming Zhang , An-Hui Huang , Hao Yin , Ying Zhang

Efficient genome editing in mammalian cells is essential for CRISPR-based therapeutics. While extensive efforts focused on combining multiple beneficial point mutations to enhance Cas9 activity, the potential of engineering surface-exposed loops remains largely underexplored. Here, we present loop engineering as a streamlined strategy to enhance Cas9 performance. Substituting loops of thermophilic AtCas9 with counterparts from mesophilic Nme1Cas9 generated the AtCas9-Z7 variant, which significantly improves nuclease and base editing efficiency. Biochemical assays showed that Mg²⁺ promotes RNP-DNA interactions, and Z7 maintains high binding affinity under magnesium-limiting condition, a common constraint for Cas9 activity in mammalian cells. Molecular dynamics simulations revealed that Z7 adopts a stable, compact conformation. Importantly, loop engineering can be combined with structure-guided point mutations to further boost activity. The resulting Z7-E78-ABE variant not only achieved a 5.76-fold increase compared to WT AtCas9 and expanded PAM recognition, while enabling editing in primary human T cells, which was not observed with WT AtCas9. Extending this strategy, loop transplantation into GeoCas9 and ThermoCas9 boosted editing efficiency by a median of 14.50-fold and 7.37-fold, respectively, at non-canonical PAMs. Collectively, these results establish loop engineering as a rational and modular approach for Cas9 optimization with therapeutic potential.

在哺乳动物细胞中进行有效的基因组编辑对于基于crispr的治疗至关重要。虽然大量的工作集中在结合多个有益的点突变来增强Cas9活性，但工程表面暴露环的潜力仍未得到充分探索。在这里，我们将循环工程作为一种简化的策略来提高Cas9的性能。将嗜热性AtCas9的环替换为中温性Nme1Cas9的对应环，生成AtCas9- z7变体，显著提高了核酸酶和碱基编辑效率。生化实验表明，Mg2+促进RNP-DNA相互作用，Z7在限镁条件下保持高结合亲和力，这是哺乳动物细胞中Cas9活性的常见限制。分子动力学模拟表明，Z7具有稳定、致密的构象。重要的是，环工程可以与结构引导的点突变相结合，以进一步提高活性。由此产生的Z7-E78-ABE变体不仅比WT AtCas9增加了5.76倍，并且扩展了PAM识别，同时能够在原代人T细胞中进行编辑，这在WT AtCas9中没有观察到。将这一策略扩展到GeoCas9和ThermoCas9中，在非规范pam中，环移植使编辑效率中位数分别提高了14.50倍和7.37倍。总的来说，这些结果确立了环工程作为具有治疗潜力的Cas9优化的合理和模块化方法。

{"title":"Loop engineering of AtCas9 for effective and broad genome editing","authors":"Yue-Lin Zhang , Dong-Chao Huang , Min Duan , Yu-Ming Zhang , An-Hui Huang , Hao Yin , Ying Zhang","doi":"10.1016/j.cellin.2025.100286","DOIUrl":"10.1016/j.cellin.2025.100286","url":null,"abstract":"<div><div>Efficient genome editing in mammalian cells is essential for CRISPR-based therapeutics. While extensive efforts focused on combining multiple beneficial point mutations to enhance Cas9 activity, the potential of engineering surface-exposed loops remains largely underexplored. Here, we present loop engineering as a streamlined strategy to enhance Cas9 performance. Substituting loops of thermophilic AtCas9 with counterparts from mesophilic Nme1Cas9 generated the AtCas9-Z7 variant, which significantly improves nuclease and base editing efficiency. Biochemical assays showed that Mg<sup>2+</sup> promotes RNP-DNA interactions, and Z7 maintains high binding affinity under magnesium-limiting condition, a common constraint for Cas9 activity in mammalian cells. Molecular dynamics simulations revealed that Z7 adopts a stable, compact conformation. Importantly, loop engineering can be combined with structure-guided point mutations to further boost activity. The resulting Z7-E78-ABE variant not only achieved a 5.76-fold increase compared to WT AtCas9 and expanded PAM recognition, while enabling editing in primary human T cells, which was not observed with WT AtCas9. Extending this strategy, loop transplantation into GeoCas9 and ThermoCas9 boosted editing efficiency by a median of 14.50-fold and 7.37-fold, respectively, at non-canonical PAMs. Collectively, these results establish loop engineering as a rational and modular approach for Cas9 optimization with therapeutic potential.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"4 6","pages":"Article 100286"},"PeriodicalIF":0.0,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145467591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitochondrial cristae remodeling: Mechanisms, functions, and pathology 线粒体嵴重塑：机制、功能和病理

Cell insight

Pub Date : 2025-10-16 DOI: 10.1016/j.cellin.2025.100285

Jianglong Yu , Yuanchun Luo , Jiacheng Lin , Zhuofan Li , Zheng Fang , He He , Chaojun Yan , Zhiyin Song

Mitochondrial cristae are the principal sites of oxidative phosphorylation and are central to mitochondria-dependent energy metabolism. Rather than static folds, cristae are dynamic bioenergetic compartments that remodel in response to physiological and stress cues. During remodeling, their number, length, width, lateral alignment, curvature/stiffness, and the geometry of crista junctions (CJs) can change. Depending on cellular context, cristae may increase in abundance, tighten or widen, and exhibit opening or closure of CJs, with corresponding effects on respiratory-chain organization and supercomplex assembly. Key regulators include OPA1 (and its proteolytic processing), the MICOS complex that scaffolds CJs, F₁Fo-ATP synthase dimerization/oligomerization that shapes high-curvature ridges, and cardiolipin, which stabilizes inner-membrane architecture. Abnormal cristae compromise electron transport, ATP production, and mitochondrial metabolism, contributing to neurodegeneration and metabolic disease etc. In this review, we synthesize current insights into the molecular control of cristae ultrastructure and its impact on mitochondrial metabolism, delineate structural features and quantitative readouts, and highlight mechanisms that govern cristae remodeling under physiological and stress conditions, with an emphasis on diseases arising from aberrant crista architecture.

线粒体嵴是氧化磷酸化的主要位点，是线粒体依赖的能量代谢的中心。嵴不是静态折叠，而是动态的生物能量隔室，可以根据生理和压力信号进行重塑。在重塑过程中，它们的数量、长度、宽度、横向排列、曲率/刚度和嵴连接（CJs）的几何形状可以改变。根据细胞环境的不同，嵴可以丰度增加，收紧或扩大，并表现出CJs的打开或关闭，从而对呼吸链组织和超复合体的组装产生相应的影响。关键的调节因子包括OPA1（及其蛋白水解过程）、支撑CJs的MICOS复合物、形成高曲率嵴的F1Fo-ATP合成酶二聚化/寡聚化，以及稳定细胞膜内部结构的心磷脂。嵴异常影响电子传递、ATP产生和线粒体代谢，导致神经退行性变性和代谢性疾病等。在这篇综述中，我们综合了目前对嵴超微结构的分子控制及其对线粒体代谢的影响的见解，描绘了结构特征和定量读数，并强调了生理和应激条件下嵴重塑的机制，重点是由异常嵴结构引起的疾病。

{"title":"Mitochondrial cristae remodeling: Mechanisms, functions, and pathology","authors":"Jianglong Yu , Yuanchun Luo , Jiacheng Lin , Zhuofan Li , Zheng Fang , He He , Chaojun Yan , Zhiyin Song","doi":"10.1016/j.cellin.2025.100285","DOIUrl":"10.1016/j.cellin.2025.100285","url":null,"abstract":"<div><div>Mitochondrial cristae are the principal sites of oxidative phosphorylation and are central to mitochondria-dependent energy metabolism. Rather than static folds, cristae are dynamic bioenergetic compartments that remodel in response to physiological and stress cues. During remodeling, their number, length, width, lateral alignment, curvature/stiffness, and the geometry of crista junctions (CJs) can change. Depending on cellular context, cristae may increase in abundance, tighten or widen, and exhibit opening or closure of CJs, with corresponding effects on respiratory-chain organization and supercomplex assembly. Key regulators include OPA1 (and its proteolytic processing), the MICOS complex that scaffolds CJs, F<sub>1</sub>Fo-ATP synthase dimerization/oligomerization that shapes high-curvature ridges, and cardiolipin, which stabilizes inner-membrane architecture. Abnormal cristae compromise electron transport, ATP production, and mitochondrial metabolism, contributing to neurodegeneration and metabolic disease etc. In this review, we synthesize current insights into the molecular control of cristae ultrastructure and its impact on mitochondrial metabolism, delineate structural features and quantitative readouts, and highlight mechanisms that govern cristae remodeling under physiological and stress conditions, with an emphasis on diseases arising from aberrant crista architecture.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"4 6","pages":"Article 100285"},"PeriodicalIF":0.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145419276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

Cell insight

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀