Cell Death and Differentiation最新文献

Adipose stem cell hierarchy was delineated by scRNA-seq analysis, revealing that ICAM-1, a glycoprotein that mediates cell-cell interaction, is a preadipocyte marker. However, the cellular and molecular mechanisms of how ICAM-1⁺ preadipocytes contribute to adipose tissue homeostasis in vivo remain unclear. To address this, Icam1^+/CreERT2 mice were generated, and it was demonstrated that ICAM-1-expressing progenitors actively participated in developing and remodeling white adipose tissue. Under a high-fat diet, both proliferation and adipogenic differentiation of ICAM-1⁺ preadipocytes increased significantly. Interestingly, ICAM-1 plays a critical role in maintaining the interaction between preadipocytes and immune cells, acting as a checkpoint on white adipogenesis. Mice lacking ICAM-1 specifically in stromal cells exhibited worsened hyperplastic obesity, showing heightened fatty acid synthesis and lipid storage in adipose tissue, and the related insulin resistance. In human adipose tissue, ICAM-1 also marked committed preadipocytes and mediated adhesion between preadipocytes and immune cells. Thus, our study shows that ICAM-1 marks preadipocytes and curbs adipogenesis by facilitating adhesion between preadipocytes and immune cells.

Although radiotherapy (RT) is used in more than 50% of cancer patients, the intrinsic radioresistance of cancer cells, characterized by metabolic adaptation, significantly limits its clinical efficacy. However, the mechanisms underlying RT resistance (RTR) remain incompletely understood. In this study, we used high-throughput metabolic CRISPR library screening and identified ABCC10 as a novel molecular contributor to RTR. Functional assays, including vesicle transport, molecular docking, and an enzyme-linked immunosorbent assay, confirmed that the R545 site of ABCC10 binds to and effluxes 2′3′-cyclic GMP–AMP (cGAMP) in an ATP-dependent manner. Mechanistically, RNA transcriptomics, along with overexpression and silencing experiments, demonstrated that ABCC10-mediated export of cGAMP suppresses the STING-TBK1-IRF3 signaling pathway. This efflux reduces RT-induced intercellular accumulation of reactive oxygen species and DNA damage. In vivo, a combination of RT and nilotinib, a potential ABCC10 inhibitor, synergistically inhibited tumor growth. In summary, we identified ABCC10 as a novel exporter of cGAMP in RTR. Our results highlight its potential role as a biomarker for predicting RT response and as a therapeutic target for overcoming RTR.

In plants, metacaspases—cysteine proteases—have gained attention for their roles in programmed cell death (PCD). However, to date, their proteolytic activity has not been established as a direct executioner of PCD, analogous to caspases in animals. In this regard, the specific executioners of PCD remain to be identified in plants, leaving the process less well understood than in animals. More recently, metacaspases have also been recognized for their roles in cellular homeostasis. This perspective explores the pro-death and pro-survival roles of plant metacaspases in plant stress responses and development. Under abiotic stress conditions, such as heat, drought or high salinity, metacaspases help maintain protein homeostasis and mitigate damage by regulating processes like the unfolded protein response. In plant immunity, metacaspases have context-dependent pro-death or pro-survival roles. Pro-survival roles include cleavage and generation of immune peptides and regulating immune receptor stability as part of immunocondensates. They have also been shown to tightly regulate immunogenic cell death after pathogen attack, although their mode of action in this context remains elusive. Developmentally, metacaspases participate in key processes that involve PCD, like xylem differentiation and lateral root cap formation, where they help control cellular remodelling. Ultimately, metacaspases are emerging as multifunctional molecules crucial to cellular integrity, immunity, and development. Understanding the balance between cell death and survival pathways in plants is crucial, as it directly impacts crop resilience to environmental stresses and pathogens, ultimately influencing food security and our dependence on plant-based resources.

ATG3 (autophagy-related gene 3), an E2 like enzyme, plays a vital role in autophagy by regulating the lipidation modification of LC3 (microtubule-associated protein 1A/1B-light chain 3). Although the level of ATG3 can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Histone deacetylase 6 (HDAC6) is involved in multiple cellular activities by regulating acetylation of its substrates such as α-tubulin and cortactin. Here, we revealed a novel function of HDAC6 in autophagy regulation by mediating the post-translational modifications of ATG3. We found that HDAC6 interacts with ATG3 and deacetylates ATG3. In addition, HDAC6 acts its ubiquitin E3 ligase activity and ubiquitinates ATG3 at lysine 272, leading to ATG3 degradation. Intriguingly, lysine 272 of ATG3 is targeted for deacetylation as well as ubiquitination by HDAC6. Further study showed that HDAC6 participates in autophagy by mediating ATG3 degradation. Taken together, our findings uncover a novel role of HDAC6 in autophagy regulation by mediating the protein modification and degradation of ATG3.

M2-like tumor-associated macrophages (TAMs) are the main immunosuppressive cells infiltrating the tumor microenvironment (TME), the activation of which is essential for cancer progression and resistance promotion to immunotherapy. However, the regulatory mechanisms underlying TAM activation have not been fully elucidated. Utilizing a CRISPR-Cas9-based genetically engineered mouse model, we discovered that USP1^fl/flLyz2^cre/+ and WDR48^fl/flLyz2^cre/+ mice exhibited decreased tumor formation and lung metastasis. Mechanistically, the USP1-WDR48 deubiquitinase complex regulated M2-TAM activation and infiltration in the TME by modulating DDX3X ubiquitination. Specifically, this complex interacted with the N-terminal RecA-like domain 1 of DDX3X, leading to K48-linked deubiquitination and stabilization of DDX3X. Then, DDX3X promoted the translation of signaling molecules Jak1 and Rac1 via its RNA helicase activity, activating the Jak1-Stat3/6 and Rac1-Akt pathways to drive M2-TAM activation. Furthermore, combined inhibition of the USP1/WDR48 and CD47/SIRPα signaling pathways showed synergistic antitumor effects in immunocompetent mice. Notably, USP1 protein expression in tumor stromal tissues independently predicts prognosis in breast cancer patients. These findings indicated the role of the USP1-WDR48 complex as a critical molecular switch controlling TAM activation, presenting novel and promising targets for breast cancer treatment.

Ripk1 plays an important role as a regulator of programmed cell death processes such as apoptosis and necroptosis and is involved in initiating pro-inflammatory NF-κB signaling. Immune tolerance depends on the proper function and homeostasis of regulatory T (Treg) cells. Here, we show that specific ablation of Ripk1 in Treg cells leads to systemically reduced Treg cell numbers resulting in spontaneous whole-body pathology. Using chimeric mice that allowed us to study Treg cells in the absence of inflammatory conditions, we observed a competitive disadvantage in vivo of Ripk1-deficient compared to Ripk1-proficient Treg cells. Furthermore, single-cell RNA sequencing revealed that Ripk1 is required for the maintenance of the effector Treg cell transcriptional signature, which is essential to prevent immune dysregulation. To overcome the limitation of low cell numbers in the chimeric mice, we isolated Treg cells from mice, in which Ripk1 could be deleted in a tamoxifen-inducible manner. Despite the strong reduction detected in Ripk1-deficient Treg cells of the chimeric mice, we did not observe impaired viability by the sole absence of Ripk1 in Treg cells from the inducible system. Of note, we observed reduced viability of activated Ripk1-deficient Treg cells in the presence of TNF. Together, these findings highlight the fundamental role of Ripk1 in maintaining immune homeostasis by preserving the highly suppressive effector Treg cells.