Cell Communication and Signaling最新文献

Background: Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency syndrome in humans, characterized by reduced leukocyte recruitment. The regulation of intracellular calcium levels in neutrophils is important for cellular processes; however, the exact role of store-operated calcium entry (SOCE) and the involvement of stromal interaction molecule (STIM) calcium sensors, and ORAI1-3 calcium channels in neutrophil activation and recruitment is unknown.

Methods: Using an acute kidney injury (AKI) model, intravital microscopy, and biochemical studies, we examined the molecular mechanisms of Ca²⁺-regulated neutrophil activation and recruitment.

Results: We demonstrate that STIM1 and ORAI1 in neutrophils are selectively required for E-selectin- and CXCL-1-, but not P-selectin-mediated activation of the β₂-integrin CD11a and neutrophil recruitment. Surprisingly, we did not detect an impact of STIM and ORAI isoform expression on neutrophil CD11b activation. Using a clinically relevant murine AKI model, we point out that STIM1- and ORAI1-deficiency in neutrophils prevents neutrophil recruitment into the kidney during sterile inflammation.

Conclusion: Thus, we uncover stimulus specific integrin regulation in neutrophils as a critical determinant of an adequate immune response and pinpoint the clinical relevance of STIM1 and ORAI1.

Background and aims: Metabolic associated fatty liver disease (MAFLD) is closely associated with metabolic disorders, including central obesity, dyslipidaemia, hypertension, hyperglycaemia and persistent abnormalities of liver function tests. Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of MAFLD, characterized by chronic inflammation and accumulation of fat in liver tissue. Currently, no pharmacological interventions specifically tailored for MASH are approved. Signal transducer and activator of transcription 1 (STAT1) is the key transcription factor of the JAK-STAT signaling pathway, participating in physiological and pathological processes such as immune regulation, inflammatory response, antiviral defense, cell proliferation and apoptosis, and plays an important regulatory role in the occurrence and development of MASH. However, the post-translational modification of STAT1 in MASH is unclarified.

Methods and results: We identified that STAT1 was increased in MASH due to the inhibition of ubiquitination levels. Mechanistically, we showed that TRIM21 directly binds to STAT1 and promotes STAT1 degradation by accelerating lysine residue at 48 site-linked ubiquitination. Through gain- and loss-of-function studies in Trim21 knockout mice and adenovirus-treated models (in vivo and in vitro), we further demonstrated TRIM21's protective role in MASH. Collectively, our investigations have revealed that TRIM21 suppresses hepatocyte steatosis relying on regulating STAT1.

Conclusion: The ubiquitination of STAT1 in MASH is regulated by TRIM21 which is a key suppressor of MASH. TRIM21 acts as a negative regulator in hepatic steatosis and offers potential therapeutic opportunities for MASH.

Large extracellular vesicles (lEVs), particularly the recently identified blebbisomes, are emerging as critical mediators of tumor progression and intercellular communication. Compared with small vesicles, lEVs exhibit pronounced heterogeneity in size, cargo composition, and mechanisms of biogenesis. While EVs of all sizes can carry proteins, nucleic acids, lipids, and metabolites, lEVs more frequently encapsulate bulky cargos-including intact organelles such as mitochondria-reflecting their size-enabled loading capacity rather than a feature unique to lEVs. These characteristics position lEVs as key regulators of immune responses, metabolic reprogramming, and the establishment of pre-metastatic niches within the tumor microenvironment. Blebbisomes, distinguished by their dynamic membrane behavior, bidirectional cargo transfer, and high expression of immunosuppressive molecules, represent a novel paradigm in extracellular communication. However, challenges persist in defining lEV subtypes, achieving efficient purification and isolation, and accurately tracking their behavior in vivo. This review systematically summarizes recent advances in lEV research in tumor biology, highlights the distinctive functions of blebbisomes, and examines their translational potential in diagnostics and therapy. Key knowledge gaps are identified, including the need for single-vesicle multi-omics, advanced lipidomics, and engineered analytical platforms. We advocate for expanded investigation into lEVs as promising targets and tools in precision oncology.

The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling-thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.

Background: Colorectal cancer (CRC) progression is fuelled by immune evasion, yet the underlying molecular mechanisms remain to be fully characterized. CD276 (B7-H3), an immune checkpoint glycoprotein frequently overexpressed in aggressive tumors, is extensively modified by glycosylation, a process known to regulate protein stability, localization, and immune interactions. However, its glycosylation-dependent functions in CRC remain unclear.

Methods: TCGA Transcriptomic data were analysed to identify glycogene alterations linked to patient prognosis. The O-glycome of advanced CRC and normal mucosa was profiled by mass spectrometry. CD276 expression and glycosylation were examined in primary tumors, lymph nodes, and metastases by immunohistochemistry, proximity ligation assays, and dual immunofluorescence. CRC proteomic datasets from PRIDE (≥ 90 cases) were reanalyzed to map CD276 immature glycosylation across differentiation states. C1GALT1 knockout CRC cell lines were generated with CRISPR-Cas9 to mimic immature glycosylation in tumors, and CD276 was silenced with siRNAs. Immunoprecipitation, lectin blotting, protein stability assays, proliferation, invasion, phosphoproteomics, and T cell co-culture experiments were used to assess functional consequences.

Results: Downregulation of B3GNT6 and C1GALT1 or C1GALT1C1 defined an immature O-glycosylation phenotype associated with poor prognosis. Glycomic profiling revealed Tn- and sialyl-Tn(sTn)-enriched glycophenotypes in both epithelial- and mesenchymal-like tumors, with subtype-specific patterns. CD276 colocalized with Tn and sTn, carried immature O-glycans absent from healthy tissues, and was enriched in right-sided and metastatic CRC, correlating with worse survival. PRIDE reanalysis suggested widespread CD276 expression and revealed differentiation-linked glycosylation, which was denser in the IgV and IgC domains of epithelial-like tumors and sparser, membrane-proximal in mesenchymal-like tumors. C1GALT1 knockout in CRC cells enhanced invasion while increasing CD276 stability and transcription, driving its overexpression. Aberrantly glycosylated CD276 promoted proliferation, invasion, kinase-driven signalling, and T cell suppression while driving cytokines toward immunosuppression. TCGA confirmed that high CD276 and low C1GALT1 expression correlated with transcriptional signatures of heightened immune checkpoint activity and T cell exhaustion.

Conclusions: Immature CD276 glycosylation promotes CRC aggressiveness and immune escape, representing a candidate prognostic biomarker and therapeutic target.