EMBO Reports最新文献

The transmembrane protein CMTM6 promotes plasma membrane expression of the immune checkpoint protein PD-L1, a key suppressor of anti-tumor immunity. Targeting CMTM6 has been proposed as a strategy to enhance tumor cell killing by reducing PD-L1 surface expression. In accord, ablation of CMTM6 in mouse cancer models was shown to efficiently suppress tumor growth, but unexpectedly in a manner partially independent of PD-L1, suggesting that CMTM6 may regulate additional proteins involved in anti-tumor immunity. Using mass spectrometry, we discovered that mouse CMTM6 strongly associates with the cell death receptor FAS and negatively regulates its surface expression in mice. Deletion of CMTM6 increases FAS plasma membrane localization and sensitizes murine cells to FAS ligand-induced cytotoxicity. However, the interaction between CMTM6 and FAS is absent in human cells due to the difference in three amino acids at the boundary of the FAS extracellular and transmembrane domains. Altogether, our findings urge caution when translating promising data regarding the targeting of CMTM6 from mouse cancer models to potential human therapies.

Intrinsically disordered regions (IDRs) are widespread in proteins, yet their evolutionary paths remain poorly understood. Using galectin, a universal carbohydrate-binding protein, we investigated how IDRs evolved and acquired their biological roles in vertebrates. Through extensive proteome-wide sequence analyses, we found that vertebrate galectin IDRs share overall amino acid compositions but differ significantly in their aromatic residue types. Using nuclear magnetic resonance (NMR) spectroscopy and lipopolysaccharide micelle assays, we demonstrated that despite these differences, IDRs from various vertebrate galectins independently converged toward a similar function: mediating agglutination via phase separation. Our data suggest that the specific types of aromatic residues within these IDRs were established early in evolution and underwent independent expansions among different vertebrate lineages. Additionally, we identified a conserved short N-terminal motif critical for promoting galectin self-association, which likely served as an incipient sequence for subsequent IDR evolution. Contrary to previous peptide studies emphasizing aromatic residue specificity, our findings highlight the evolutionary preference for increasing motif repetition over residue-type optimization to achieve functional fitness.

Paneth cells are defensive cells in the intestinal tract, which secrete niche factors and antimicrobial peptides (AMPs) to maintain the small intestinal stem cell niche and immune homeostasis. Here, we show that Vestigial-like family member 4 (VGLL4) plays a pivotal role in maintaining small intestinal homeostasis and in regulating Paneth cells. VGLL4 expression is downregulated in response to irradiation and DSS-induced colitis. Consistently, public datasets of human colitis show reduced VGLL4 expression. Loss of VGLL4 in the intestinal epithelium decreases Paneth cell numbers and AMPs production, and triggers gut microbiota dysbiosis, impairing intestinal regenerative capacity. Mechanistically, VGLL4 forms a complex with TEAD4 and ATOH1, stimulating GFI1 expression and promoting Paneth cell differentiation. Furthermore, VGLL4 forms a complex with TEAD4 and TCF4 to induce defensin expression, thereby maintaining microbiota composition. Collectively, our findings uncover novel roles for VGLL4 in intestinal homeostasis.

Cell fate decisions in the early embryo rely on reciprocal transcriptional networks that balance pluripotency with lineage commitment. NANOG is essential for directing the epiblast-primitive endoderm (PrE) fate choice, but the molecular mechanisms underlying its repressive activity remain incompletely understood. Here we show that NANOG partners with TBX3 and the PRC2 complex to maintain embryonic stem cell (ESC) identity by silencing PrE genes through newly identified distal enhancers. Loss of Nanog reduces PRC2-mediated repression of Gata6, initiating its expression independently of TBX3. Subsequent TBX3 upregulation enables its association with GATA6, driving a feed-forward programme that activates Gata6, Gata4 and Sox17 and promotes PrE differentiation. Thus, NANOG suppresses PrE fate not only by direct repression but also by preventing TBX3 from switching partners. These findings define a Nanog-Tbx3-Gata6 regulatory axis that integrates enhancer control, chromatin regulation and transcription factor redeployment to couple ESC maintenance with lineage commitment.

Disrupted proteostasis causes various degenerative diseases, and organelle homeostasis is therefore maintained by elaborate mechanisms. Endoplasmic reticulum (ER) stress-induced preemptive quality control (ERpQC) counteracts stress by reducing ER load through inhibiting the translocation of newly synthesized proteins into the ER for their rapid degradation in the cytoplasm. Here, we show that Sec61β, a translocon component, prevents the overproduction of ERpQC substrates, allowing for their efficient degradation by the proteasome. Sec61β inhibits the binding of translation initiation factor eIF4E to the mRNA 5' cap structure by recruiting E3 ligase ARIH1 and eIF4E-homologous protein 4EHP, resulting in selective translational repression of ERpQC substrates. Sec61β deficiency causes overproduction of ERpQC substrates and reduces proteasome activity, leading to cytoplasmic aggresome formation. We also show that Sec61β deficiency causes motor dysfunction in zebrafish, which is restored by exogenous ARIH1 expression. Collectively, translational repression of ERpQC substrates by the Sec61β-ARIH1 complex contributes to maintain ER and cytoplasmic proteostasis.

Mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from nutrients, growth factors, and cellular stress to regulate biosynthesis and maintain homeostasis. Dysregulated mTORC1 disrupts stem cell homeostasis and impairs cell fate transitions in vivo and in vitro. Previous studies have shown that mTORC1 hyperactivation promotes nuclear translocation of TFE3, blocking pluripotency exit in both mouse and human naïve embryonic stem cells. Similarly, our earlier work has demonstrated that sustained mTORC1 activation impedes somatic cell reprogramming via the transcriptional coactivator PGC1α. This raises the question of how mTORC1 coordinates gene transcription across distinct transitions in pluripotent cells. Here, we show that TFE3 mediates the transcriptional blockade induced by mTORC1 hyperactivation during reprogramming. Notably, during both pluripotency exit and reprogramming, TFE3 recruits the NuRD corepressor complex to repress genes essential for cell fate transitions. These findings uncover a shared mechanism by which mTORC1 and TFE3 regulate stem cell identity, highlighting the dual regulatory role of TFE3 and its potential implications in development, aging, and tumorigenesis.

Mitophagy maintains mitochondrial homeostasis through the selective degradation of damaged or excess mitochondria. Recently, we identified mitofissin/Atg44, a mitochondrial intermembrane space-resident fission factor, which directly acts on lipid membranes and drives mitochondrial fission required for mitophagy in yeast. However, it remains unclear whether mitofissin is sufficient for mitophagy-associated mitochondrial fission and whether other factors act from outside mitochondria. Here, we identify a mitochondrial outer membrane-resident mitofissin-like microprotein required for mitophagy, and we name it mitofissin 2/Mfi2 based on the following results. Overexpression of an N-terminal Atg44-like region of Mfi2 induces mitochondrial fragmentation and partially restores mitophagy in atg44Δ cells. Mfi2 binds to lipid membranes and mediates membrane fission in a cardiolipin-dependent manner in vitro, demonstrating its intrinsic mitofissin activity. Coarse-grained molecular dynamics simulations further support the stable interaction of Mfi2 with cardiolipin-containing bilayers. Genetic analyses reveal that Mfi2 and the dynamin-related protein Dnm1 independently facilitate mitochondrial fission during mitophagy. Thus, Atg44 and Mfi2, two mitofissins with distinct localizations, are required for mitophagy-associated mitochondrial fission.

Functional traits shape ecological niches, yet the interplay between nanoscale structural modifications, sexual dimorphism, and habitat range remains poorly understood. In fireflies, cuticular nanostructures that enhance bioluminescent signaling efficiency also impose ecological constraints. Anti-reflective nanocoatings improve cuticle transparency and optical performance but typically increase surface adhesion, reducing fitness. In Luciola lusitanica, this trade-off is mitigated by temperature-sensitive nanocoatings that form only within a narrow thermal range, limiting habitat expansion. This study presents the first thermodynamic analysis of environmentally constrained nanocoating formation, demonstrating how small temperature fluctuations can destabilize protein-lipid self-assembly. These findings link nanoscale biophysics to ecological resilience, providing a framework to understand how the environmental sensitivity of structural self-organization shapes adaptation, species distribution, and evolutionary potential.

Myocardial ischemia-reperfusion (I/R) injury remains a significant challenge in cardiovascular medicine, with its molecular mechanisms still not fully understood. Screening the GEO and Comparative Toxicogenomics Database as well as spatial multi-omics data, we identify Cdkn2a, encoding p16^INK4a, as a determinant in I/R injury. Cdkn2a expression is elevated in the myocardium of ischemic cardiomyopathy patients and p16^INK4a protein is enriched in cardiomyocytes within ischemic zones of myocardial infarction tissues. We find that p16^INK4a is consistently upregulated in both in vivo and in vitro I/R models, promoting apoptosis in neonatal rat cardiomyocytes (NRCMs) and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) exposed to oxygen-glucose deprivation/reperfusion (OGD/R). p16^INK4a inhibition confers cellular protection, an effect also observed in in vivo I/R injury models. Mechanistically, p16^INK4a promotes binding of the RNA-binding protein CUGBP1 to the GRE sequence of Npas2 mRNA reducing its stability and translation, likely by inhibiting CDK4. This regulation impairs transcription of the Nasp2 target Slco1a4 and consequently bile acid transport, resulting in accumulation of intracellular bile acids and apoptosis. These findings identify p16^INK4a-regulated bile acid transport as a driver of cardiac I/R injury.