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Loss of the conserved switch III region in a G protein leads to severe pediatric encephalopathy G蛋白保守开关III区缺失可导致严重的儿科脑病

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-28 DOI: 10.1126/scisignal.adu9383

Mikhail Savitsky, Yonika A. Larasati, Gonzalo P. Solis, Alexey Koval, Ana Camacho, Noemí Núñez, Olivier Patat, Elisabeth Wallach, Serena Galosi, Maria Novelli, Simone Martinelli, Vincenzo Leuzzi, Vladimir L. Katanaev

The α subunits of heterotrimeric guanine nucleotide–binding proteins (G proteins) in G protein–coupled receptor (GPCR) pathways operate as gate switches by cycling through inactive GDP-bound and active GTP-bound states. Three flexible regions (switches I to III) of Gα subunits undergo the most substantial conformational rearrangements and determine interactions with receptors, signaling regulators, and effectors. Here, we describe three patients with severe pediatric encephalopathy harboring c.723+1G>A or c.723+2T>A variants in the splicing donor site of intron 6 of GNAO1, the gene encoding the major neuronal G protein α subunit Gα_o. These substitutions destroyed the conserved GU sequence of the pre-mRNA and rendered the donor site unrecognizable, prompting cryptic splice site engagement and production of the dominant pathogenic Gα_o[V234_T241del] variant, which lacked switch III (amino acid residues 232 to 243 in Gα_o). Structural, biochemical, and cellular analyses characterized V234_T241del as a strong neomorphic variant that was severely deficient in guanine nucleotide handling and cellular interactions and sensitive to zinc salts, an emerging targeted treatment for a GNAO1 encephalopathy subgroup. Our studies provide pathological and molecular insights into the function and effect of removal of an entire switch region in 1 of the 16 human G protein α subunits that underlie multiple physiological processes and diverse pathologies.

G蛋白偶联受体（GPCR）通路中异三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）的α亚基作为门开关，在无活性的gdp结合状态和活性的gtp结合状态之间循环。Gα亚基的三个柔性区域（开关I至III）经历了最实质性的构象重排，并决定了与受体、信号调节因子和效应物的相互作用。本研究中，我们描述了三例严重小儿脑病患者，其基因编码主要神经元G蛋白α亚基Gαo的GNAO1内含子6剪接供体位点存在c.723+1G>；A或c.723+2T>；A变异。这些取代破坏了前mrna的保守的GU序列，使供体位点无法识别，促使隐剪接位点结合并产生显性致病性Gαo[V234_T241del]变体，该变体缺乏开关III （Gαo中的氨基酸残基232至243）。结构、生化和细胞分析表明，V234_T241del是一种强新形态变异，严重缺乏鸟嘌呤核苷酸处理和细胞相互作用，对锌盐敏感，是GNAO1脑病亚群的一种新兴靶向治疗方法。我们的研究为16个人类G蛋白α亚基中1个的整个开关区去除的功能和影响提供了病理和分子上的见解，这些亚基是多种生理过程和多种病理的基础。

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引用次数: 0

Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria 在没有肠道细菌的情况下，肠道来源的山梨醇会导致脂肪变性肝病

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-28 DOI: 10.1126/scisignal.adt3549

Madelyn M. Jackstadt, Ronald Fowle-Grider, Mun-Gu Song, Matthew H. Ward, Madison Barr, Kevin Cho, Hector H. Palacios, Samuel Klein, Leah P. Shriver, Gary J. Patti

Metabolic dysfunction–associated steatotic liver disease (MASLD) is linked to a shift in the composition of the gut microbiome. Here, we found that depletion of the gut microbiome in adult zebrafish led to the development of steatotic liver disease in animals on standard diets. Using metabolomics and isotope tracing, we found that dietary glucose was converted to sorbitol by host intestinal cells. Although bacteria degraded sorbitol in control animals, sorbitol was transferred to the livers of fish when the gut microbiome had been depleted. Within the liver, sorbitol was converted into fructose 1-phosphate, which subsequently activated glucokinase and increased glycolytic flux, leading to increased hepatic glycogen and fat content. Inhibition of sorbitol production in microbiome-depleted animals was sufficient to prevent the development of steatotic liver, and colonizing the intestines of microbiome-depleted fish with sorbitol-degrading Aeromonas bacterial strains rescued the steatotic liver phenotype. Conversely, exogenous administration of high concentrations of sorbitol phenocopied gut microbiota depletion and induced hepatic steatosis. Together, these findings show that sorbitol-degrading bacteria in the gut protect against steatotic liver disease and suggest that excessive intake of dietary sorbitol may pose a risk for the development of MASLD.

代谢功能障碍相关的脂肪变性肝病（MASLD）与肠道微生物组组成的改变有关。在这里，我们发现成年斑马鱼肠道微生物群的消耗导致标准饮食动物脂肪变性肝病的发展。利用代谢组学和同位素示踪，我们发现膳食葡萄糖通过宿主肠细胞转化为山梨醇。虽然在对照动物中，细菌降解了山梨醇，但当肠道微生物群耗尽时，山梨醇被转移到鱼的肝脏中。在肝脏内，山梨醇转化为果糖1-磷酸，随后激活葡萄糖激酶，增加糖酵解通量，导致肝糖原和脂肪含量增加。在微生物组缺失的动物中抑制山梨糖醇的产生足以防止脂肪变性肝的发展，并且在微生物组缺失的鱼的肠道中定植山梨糖醇降解气单胞菌菌株挽救了脂肪变性肝的表型。相反，外源性高浓度山梨醇会引起肠道菌群耗竭和肝脂肪变性。总之，这些发现表明，肠道中的山梨糖醇降解细菌可以预防脂肪变性肝病，并提示饮食中过量摄入山梨糖醇可能会导致MASLD的发生。

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引用次数: 0

Sensory support for stem cells 干细胞的感官支持

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-28 DOI: 10.1126/scisignal.aed2818

Annalisa M. VanHook

Sensory neurons promote bone homeostasis and repair by providing osteopontin to skeletal stem cells.

感觉神经元通过向骨骼干细胞提供骨桥蛋白来促进骨稳态和修复。

引用次数: 0

Injury-induced niche factors Cxcl12 and Shh/Ihh coordinate suture stem cell activation during calvarial bone regeneration 损伤诱导的生态位因子Cxcl12和Shh/Ihh在颅骨骨再生过程中协调缝合干细胞的激活

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-21 DOI: 10.1126/scisignal.adw7107

Bo Li, Takehito Ouchi, Jie Liu, Yingzi Yang

Stem cells reside in niches that determine how they respond to injury to expand in number, migrate to the injury site, and differentiate into cells to regenerate lost tissue. Suture stem cells (SuSCs) are important for homeostasis and regeneration of cranial bone and can be used as a model to understand stem cell regulation for bone regeneration at a distance. Using a mouse cranial bone injury model, we identified the chemokine Cxcl12 and the Hedgehog family ligands Shh and Ihh as injury-induced niche factors that coordinately promoted the proliferation, directional migration, and osteoblastic differentiation of the Gli1⁺ subset of SuSCs from the sagittal suture. Cxcl12 was constitutively produced in the SuSC niche, induced at the injury site, and activated its cognate receptor Cxcr4 on Gli1⁺ SuSCs to stimulate Gli1⁺ SuSC proliferation and migration to the injury site. Cxcl12-Cxcr4 signaling also induced the production of Shh and Ihh, which promoted Gli1⁺ SuSC proliferation and osteoblastic differentiation. Furthermore, expressing loss- or gain-of-function mutant forms of the G protein Gα_s, which cause inherited diseases characterized by cranial bone defects, led to aberrant Cxcl12, Shh, and Ihh signaling during regeneration and resulted in cranial bone phenotypes similar to those in human patients. Our results indicate that the injury-induced niche factors Cxcl12, Shh, and Ihh orchestrate SuSC activation and migration to promote injury repair and suggest that disrupting this system impairs regeneration and contributes to human disease.

干细胞存在于小生境中，这决定了它们如何对损伤做出反应，以扩大数量，迁移到损伤部位，并分化成细胞以再生失去的组织。缝合干细胞（SuSCs）对于颅骨的稳态和再生非常重要，可以作为一种模型来了解干细胞对骨再生的调控。通过小鼠颅骨损伤模型，我们发现趋化因子Cxcl12和Hedgehog家族配体Shh和Ihh是损伤诱导的生态位因子，它们协调促进了矢状缝合线上的胶质细胞Gli1+亚群的增殖、定向迁移和成骨分化。Cxcl12在SuSC生态位中组成性产生，在损伤部位诱导，激活Gli1+ SuSC上的同源受体Cxcr4，刺激Gli1+ SuSC增殖并向损伤部位迁移。Cxcl12-Cxcr4信号传导也诱导Shh和Ihh的产生，促进Gli1+ SuSC增殖和成骨细胞分化。此外，表达功能缺失或功能获得的G蛋白Gαs突变形式，导致以颅骨缺陷为特征的遗传性疾病，导致再生过程中异常的Cxcl12， Shh和Ihh信号，并导致与人类患者相似的颅骨表型。我们的研究结果表明，损伤诱导的生态位因子Cxcl12、Shh和Ihh协调SuSC的激活和迁移，以促进损伤修复，并表明破坏该系统会损害再生并导致人类疾病。

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引用次数: 0

PARP1-mediated PARylation of TEAD4 stabilizes the YAP1-TEAD4 complex and promotes growth and immune evasion in breast cancer cells parp1介导的TEAD4的PARylation稳定了YAP1-TEAD4复合物并促进乳腺癌细胞的生长和免疫逃避

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-21 DOI: 10.1126/scisignal.adx2532

Yibo Guo, Gaoqing Song, Hailin Zou, Liangxin Lu, Xuyin Dai, Chuannan Sun, Haoming Chen, Tongyu Tong, Mengjun Huang, Mengyuan Zhu, Liang Deng, Yulong He, Changhua Zhang, Juan Luo, Peng Li

The transcriptional coactivator YAP1 regulates numerous biological processes, including organ size control and tissue homeostasis. Although its hyperactivity promotes tumor development and progression, YAP1 itself is not yet druggable. Here, we found that the poly(ADP-ribose) polymerase PARP1 promoted the transcriptional activity of YAP1-TEAD4 complexes that mediate breast cancer cell stemness, metastatic behavior, and evasion of antitumor immunity. This PARP1-mediated mechanism was independent of its role in the DNA damage response. Specifically, PARP1 directly interacted with and promoted the formation of the YAP1-TEAD4 complex by PARylating TEAD4 at a conserved Arg-Lys sequence. This PARP1-enhanced YAP1-TEAD4 binding attenuated the interaction between YAP1 and the E3 ubiquitin ligase CRL4^DCAF12, thus preventing its ubiquitylation and degradation. Furthermore, the abundance of PARP1 protein correlated with that of YAP1 and the immune checkpoint protein PD-L1 in breast cancer tissues and cell lines. In a mouse model of triple-negative breast cancer, pharmacological inhibition of PARP1 enhanced the ability of antibody blockade of PD-L1 to increase cytolytic and tumor-suppressive T cell infiltration and reduce tumor growth. The findings reveal a mechanism that promotes YAP1-TEAD4 transcriptional activity and immune escape in breast cancer cells and is targetable with clinically approved therapies.

转录共激活因子YAP1调节许多生物过程，包括器官大小控制和组织稳态。虽然YAP1的过度活性促进肿瘤的发生和进展，但它本身还不能被药物治疗。在这里，我们发现聚（adp -核糖）聚合酶PARP1促进了YAP1-TEAD4复合物的转录活性，这些复合物介导乳腺癌细胞的干细胞性、转移行为和抗肿瘤免疫的逃避。这种parp1介导的机制独立于其在DNA损伤应答中的作用。具体来说，PARP1通过在一个保守的Arg-Lys序列上聚合TEAD4，直接与YAP1-TEAD4复合物相互作用并促进其形成。这种parp1增强的YAP1- tead4结合减弱了YAP1与E3泛素连接酶CRL4DCAF12之间的相互作用，从而阻止了其泛素化和降解。此外，乳腺癌组织和细胞系中PARP1蛋白的丰度与YAP1和免疫检查点蛋白PD-L1的丰度相关。在小鼠三阴性乳腺癌模型中，药物抑制PARP1可增强抗体阻断PD-L1的能力，增加细胞溶解和肿瘤抑制T细胞浸润，降低肿瘤生长。这些发现揭示了促进乳腺癌细胞中YAP1-TEAD4转录活性和免疫逃逸的机制，并且是临床批准的靶向治疗。

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引用次数: 0

The E3 ubiquitin ligase ZNRF3 restricts WNT receptor complex activity by stimulating the selective degradation of WNT-engaged FZD E3泛素连接酶ZNRF3通过刺激WNT参与的FZD的选择性降解来限制WNT受体复合物的活性

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-14 DOI: 10.1126/scisignal.adv1529

Bo Lu, Feng Cong

Ligands of the WNT family induce formation of the WNT receptor signalosome and promote stabilization of the transcriptional coactivator β-catenin. The homologous transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 inhibit WNT-dependent stabilization of β-catenin by stimulating the degradation of the WNT receptor FZD, whereas the secreted R-spondin proteins promote the stabilization of FZD by inducing the degradation of ZNRF3 and RNF43. Here, we report that the R-spondin–induced stabilization of β-catenin in HEK293 cells was not mimicked by FZD overexpression, highlighting a gap in our understanding of this important regulatory mechanism. Contrary to the conventional view that ZNRF3 constitutively mediates the ubiquitylation and degradation of FZD, we found that ZNRF3-induced FZD degradation depended on endogenous WNT and that ZNRF3 selectively degraded WNT-engaged FZD. WNT enhanced the association between FZD and the intracellular adaptor protein DVL, and DVL subsequently recruited ZNRF3 to FZD to promote FZD degradation. Our data suggest that WNT signaling actively restricts itself through ZNRF3-dependent degradation of WNT-engaged FZD and that R-spondin enhances WNT signaling by prolonging the action of the WNT-engaged FZD complex, rather than by simply increasing the abundance of FZD on the cell surface.

WNT家族的配体诱导WNT受体信号体的形成，并促进转录辅激活因子β-连环蛋白的稳定。同源的跨膜E3泛素连接酶ZNRF3和RNF43通过刺激WNT受体FZD的降解来抑制WNT依赖性β-catenin的稳定，而分泌的R-spondin蛋白通过诱导ZNRF3和RNF43的降解来促进FZD的稳定。在这里，我们报道了r -spondin诱导的HEK293细胞中β-catenin的稳定并没有被FZD过表达所模仿，这突出了我们对这一重要调节机制的理解上的差距。与ZNRF3组成型介导FZD泛素化和降解的传统观点相反，我们发现ZNRF3诱导的FZD降解依赖于内源性WNT，并且ZNRF3选择性地降解WNT参与的FZD。WNT增强了FZD与细胞内接头蛋白DVL之间的联系，DVL随后将ZNRF3募集到FZD中，促进FZD的降解。我们的数据表明，WNT信号通过依赖于znrf3的WNT-接合FZD的降解来主动限制自身，R-spondin通过延长WNT-接合FZD复合物的作用来增强WNT信号，而不是简单地增加细胞表面FZD的丰度。

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引用次数: 0

STING’s cysteine modifications STING的半胱氨酸修饰

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-14 DOI: 10.1126/scisignal.aec8984

John F. Foley

Coordinated posttranslational modifications of cysteine residues regulate STING oligomerization and function.

半胱氨酸残基的协调翻译后修饰调节STING寡聚化和功能。

引用次数: 0

Senataxin promotes recombination fidelity during antigen receptor gene diversification Senataxin促进抗原受体基因多样化过程中的重组保真度

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-14 DOI: 10.1126/scisignal.adv8801

Alice Billie Libri, Jinglong Wang, Timea Marton, Wei Yu, François Dossin, Gabriel Balmus, Bernardo Reina-San-Martin, Richard Frock, Chloé Lescale, Ludovic Deriano

Antigen receptor diversity depends on the assembly of variable (V), diverse (D), and joining (J) exons in genes encoding immunoglobulins (Igs) and T cell receptors (TCRs). During V(D)J recombination, DNA double-strand breaks (DSBs) introduced by the RAG1/2 nuclease complex are repaired by the process of nonhomologous end-joining (NHEJ). We hypothesized that functional redundancies between NHEJ and the chromatin DSB response, which depends on the kinase ATM, potentially masked the activity of additional factors that regulate V(D)J recombination. We performed targeted CRISPR-Cas9 knockout screens for genes implicated in V(D)J recombination in pro-B cells that were either untreated or treated with an ATM inhibitor. We found that loss of the RNA/DNA helicase senataxin (SETX) impaired V(D)J recombination and led to the formation of aberrant hybrid joints between coding ends and signal ends, both in vitro and in mice. The loss of SETX in a background deficient in the NHEJ factor XLF or in which ATM was inhibited led to substantial impairment of V(D)J recombination and to the presence of unsealed coding ends. SETX limited aberrant activation-induced cytidine deaminase (AID)–induced DNA end-joining between Igh-containing alleles during the process of class-switch recombination. Together, our findings reveal a previously uncharacterized role for SETX in promoting recombination fidelity during antigen receptor gene diversification.

抗原受体的多样性取决于编码免疫球蛋白（Igs）和T细胞受体（TCRs）的基因中可变(V)、多样(D)和连接(J)外显子的组装。在V(D)J重组过程中，RAG1/2核酸酶复合体引入的DNA双链断裂（DSBs）通过非同源末端连接（NHEJ）过程修复。我们假设NHEJ和染色质DSB反应之间的功能冗余（依赖于激酶ATM）可能掩盖了调节V(D)J重组的其他因子的活性。我们对未处理或使用ATM抑制剂处理的前b细胞中与V(D)J重组相关的基因进行了靶向CRISPR-Cas9敲除筛选。我们发现RNA/DNA解旋酶senataxin （SETX）的缺失损害了V(D)J重组，导致编码端和信号端之间形成异常的杂交关节，无论是在体外还是在小鼠体内。在NHEJ因子XLF缺乏或ATM被抑制的背景下，SETX的缺失会导致V(D)J重组的严重损伤和编码端未密封的存在。SETX限制了类转换重组过程中异常激活诱导的胞苷脱氨酶（AID）诱导的含高等位基因之间的DNA末端连接。总之，我们的研究结果揭示了SETX在抗原受体基因多样化过程中促进重组保真度的先前未被描述的作用。

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引用次数: 0

An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas 异位的刺猬信号轴驱动遗传性多发性骨软骨瘤小鼠模型的定向肿瘤生长

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-07 DOI: 10.1126/scisignal.adu6357

Sarah E. Catheline, Christina Mundy, Cheri Saunders, Sadhana Ramesh, Kelly A. Shaughnessy, Juliet Chung, Eiki Koyama, Maurizio Pacifici

Osteochondromas characterize the rare pediatric disorder hereditary multiple osteochondromas (HMO). The tumors originate from the growth plate perichondrium along skeletal elements, appear first as ectopic cartilage, and then grow unidirectionally, colliding with and damaging surrounding structures. HMO is caused by mutations that affect the heparan sulfate (HS) synthases EXT1 or EXT2, leading to HS deficiency and aberrant activity of HS-binding growth factors. We investigated the signaling pathways and mechanisms underlying tumor growth in HMO using mice with conditional Ext1 deficiency in the growth plate and perichondrium. Developing tumors displayed active Hedgehog (Hh) signaling within their cartilaginous moiety and the presence of parathyroid hormone–related protein (PTHrP) at their distal edge, generating an ectopic Hh-PTHrP axis orthogonal to the one directing normal bone lengthening at the adjacent growth plate. In Ext1 mutants, loss of the Hh signaling effector Smoothened (Smo) reduced tumor growth, whereas heterozygous loss of the Smo inhibitor Patched1 (Ptch1) increased tumor growth. Two HS-binding growth factors that promote normal cartilage growth in the growth plate, BMP2 and activin A, did not exert their normal prochondrogenic activity when Hh signaling was blocked, demonstrating that Hh signaling is essential for chondrogenesis. Together, our findings show that osteochondromas usurp a physiological signaling mechanism to guide and propel their directional outgrowth, enabling them to damage surrounding tissues, and suggest potential targets for therapeutic intervention.

骨软骨瘤是罕见的儿童疾病遗传性多发性骨软骨瘤（HMO）。肿瘤起源于生长板软骨膜，沿骨骼元素，首先表现为异位软骨，然后单向生长，与周围结构发生碰撞和损伤。HMO是由影响硫酸肝素合成酶EXT1或EXT2的突变引起的，导致HS缺乏和HS结合生长因子的异常活性。我们利用生长板和软骨膜条件Ext1缺失的小鼠，研究了HMO肿瘤生长的信号通路和机制。发展中的肿瘤在其软骨部分显示活跃的Hedgehog （Hh）信号，在其远端边缘存在甲状旁腺激素相关蛋白（PTHrP），产生异位的Hh-PTHrP轴，与相邻生长板上指导正常骨延长的轴正交。在Ext1突变体中，Hh信号效应因子Smoothened （Smo）的缺失降低了肿瘤生长，而Smo抑制剂Patched1 （Ptch1）的杂合缺失则增加了肿瘤生长。当Hh信号被阻断时，促进生长板中正常软骨生长的两种hs结合生长因子BMP2和激活素A没有发挥其正常的促软骨生成活性，这表明Hh信号对软骨形成至关重要。总之，我们的研究结果表明，骨软骨瘤篡取生理信号机制来指导和推动其定向生长，使它们能够损害周围组织，并提出了治疗干预的潜在目标。

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引用次数: 0

Phosphorylation of RYR1 at Ser2902 decreases Ca2+ leak in skeletal muscle and susceptibility to malignant hyperthermia and heat stroke RYR1 Ser2902位点的磷酸化减少骨骼肌Ca2+泄漏和对恶性高热和中暑的易感性

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-07 DOI: 10.1126/scisignal.adx3087

Rachel Sue Zhen Yee, Chang Seok Lee, Ting Chang, Sung Yun Jung, Omar Yousif, Courtney Cavazos, John Colyer, Filip Van Petegem, George G. Rodney, Susan L. Hamilton

Ryanodine receptor 1 (RYR1) is the sarcoplasmic reticulum (SR) Ca²⁺ release channel required for both skeletal muscle contraction and Ca²⁺ leak. Mutations in RYR1 cause malignant hyperthermia susceptibility (MHS) and enhanced sensitivity to heat stroke (ESHS), which can result in death due to excessive skeletal muscle thermogenesis upon exposure to volatile anesthetics or heat. Here, we investigated the molecular and physiological functions of phosphorylation of RYR1 at Ser²⁹⁰² by the kinase striated muscle preferentially expressed protein (SPEG). Muscle from SPEG-deficient mice expressing RYR1 with a Ser²⁹⁰²→Asp²⁹⁰² (S2902D) point mutation to mimic phosphorylation by SPEG showed decreased SR Ca²⁺ sparks. Muscle from mice homozygous for the S2902D point mutation had reduced SR Ca²⁺ transients and small changes in force generation but overall mild phenotypic changes. YS mice, which are heterozygous for a Tyr⁵²⁴→Ser⁵²⁴ point mutation in RYR1, show increased Ca²⁺ leak and are a model of MHS and ESHS. Crossing YS mice with S2902D mice led to decreased SR Ca²⁺ leak and desensitized the mice to both volatile anesthetics and heat. Thus, SPEG inhibits SR Ca²⁺ leak in skeletal muscle by phosphorylating Ser²⁹⁰² on RYR1, and mutation of Ser²⁹⁰² to Asp²⁹⁰² to mimic this phosphorylation event rescues YS mice from heat-induced death.

Ryanodine受体1 （RYR1）是骨骼肌收缩和Ca2+泄漏所需的肌浆网（SR） Ca2+释放通道。RYR1的突变导致恶性热疗易感性（MHS）和对中暑（ESHS）的敏感性增强，这可能导致骨骼肌在暴露于挥发性麻醉剂或高温时过度产热而死亡。在这里，我们研究了激酶横纹肌优先表达蛋白（SPEG）磷酸化RYR1 Ser2902位点的分子和生理功能。通过Ser2902→Asp2902 （S2902D）点突变表达RYR1以模拟SPEG磷酸化的SPEG缺陷小鼠的肌肉显示SR Ca2+火花降低。S2902D点突变纯合小鼠肌肉的SR Ca2+瞬态减少，力产生的变化很小，但总体上表型变化轻微。YS小鼠在RYR1中Tyr524→Ser524点突变为杂合，Ca2+泄漏增加，是MHS和ESHS的模型。YS小鼠与S2902D小鼠杂交可减少SR Ca2+泄漏，并使小鼠对挥发性麻醉剂和热脱敏。因此，SPEG通过磷酸化RYR1上的Ser2902来抑制骨骼肌中SR Ca2+泄漏，Ser2902突变为Asp2902来模拟这一磷酸化事件，从而拯救YS小鼠免于热致死亡。

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引用次数: 0