Cell Death and Differentiation最新文献

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is usually diagnosed at a late stage and has a modest clinical response and poor prognosis. Therefore, identifying targets for the effective treatment of PDAC is particularly important. STAM-binding protein (STAMBP) is a JAMM metalloprotease of the deubiquitinase (DUB) family that typically regulates the stabilization and trafficking of substrates in a range of cell types by specifically removing ubiquitin chains. However, its roles in the initiation and progression of PDAC remain unclear. Here, we found that STAMBP is highly expressed in PDAC and is associated with a poor prognosis. STAMBP facilitates the proliferation and migration of PDAC cells and the growth of pancreatic cancer xenograft tumours in mice. We then identified the cochaperone BAG3, which plays a pivotal role in tumourigenesis, as a potential substrate of STAMBP using mass spectrometry (MS). Mechanistically, STAMBP interacts with BAG3 and promotes its stabilization by removing its K63-linked polyubiquitin chains. The Lys29 and Lys60 residues of BAG3 are essential for the K63-linked ubiquitination of BAG3. Moreover, a phosphorylation-dependent mechanism of STAMBP was identified as follows: STAMBP is phosphorylated by IKKα at Ser2 without affecting STAMBP protein abundance, and this phosphorylation enables it to deubiquitinate BAG3. In addition, we found that STAMBP deficiency effectively increases cisplatin/oxaliplatin sensitivity in PDAC. Overall, IKKα phosphorylates STAMBP at Ser 2, which activates STAMBP to deubiquitinase BAG3, thus resulting in an IKKα/STAMBP/BAG3 signaling axis that promotes PDAC progression. STAMBP might serve as a potential therapeutic target for PDAC therapy.

Cancer-associated fibroblasts (CAFs) transdifferentiated from hepatic stellate cells (HSCs) are a critical determinant of liver metastasis of colorectal cancer (CRC). However, the mechanisms behind transforming growth factor β (TGF-β)-stimulated activation of HSCs into CAFs remain poorly understood. Immunoprecipitation coupled with mass spectrometry identified tuftelin 1 (TUFT1) as a novel TGF-β receptor II (TβRII) binding protein in primary human HSCs and immortalized LX2 cells. TUFT1 interacts with TβRII via its fragments (amino acids 1-86, 87-157), protecting TβRII from lysosomal degradation to facilitate TGF-β signaling and myofibroblastic activation of HSCs. Mechanistically, TUFT1 competes with caveolin-1 for TβRII binding, retrieving TβRII from the lipid rafts/caveolae-mediated degradation pathway and sorting it into the endosome-mediated trafficking and signaling pathway. Clinically, TUFT1 expression was confirmed in the CAFs of patient-derived colorectal cancer liver metastasis (CRCLM) tissues. Both protein and transcript analyses revealed higher TUFT1 expression in the CAFs of CRCLM than in HSCs. Furthermore, bulk RNA sequencing indicated that knocking down TUFT1 altered the TGF-β transcriptome of HSCs and suppressed HSC expression of tumor-promoting factors. In HSC/CRC co-implantation and portal vein tumor injection mouse models, targeting TUFT1 of HSCs inhibited HSC activation and restricted CRC growth in both subcutaneous and hepatic sites. Taken together, our findings uncover the novel function of TUFT1 in the hepatic tumor microenvironment, highlighting its role as a critical regulator of HSC activation and the pro-metastatic hepatic niche via promoting TβRII protein stability. Targeting TUFT1 in HSCs presents a promising therapeutic approach for combating CRCLM.

Excessive neutrophil activation and neutrophil extracellular trap (NET) release drive systemic inflammation and organ injury in sepsis, yet the upstream regulatory pathways remain incompletely defined. Here, we identify epidermal growth factor receptor (EGFR) as a critical neutrophil-intrinsic regulator of NETosis. EGFR expression was markedly elevated in neutrophils from patients with sepsis and correlated with disease severity. Neutrophil-specific EGFR deletion in mice improved survival after polymicrobial sepsis by reducing cytokine storm, tissue injury, and NET formation. Mechanistically, EGFR associated with CCAAT/enhancer-binding protein beta (CEBPβ) and recruited Mitogen-activated protein kinase 14 (MAPK14) to phosphorylate CEBPβ, promoting its nuclear localization and transcriptional activation of peptidoglycan recognition protein 1 (PGLYRP1). Elevated PGLYRP1, in turn, amplified NETs release via autocrine engagement of triggering receptor expressed on myeloid cell-1 (TREM-1), establishing a feed-forward inflammatory loop. Administration of recombinant PGLYRP1 or forced CEBPβ overexpression reversed the protection conferred by EGFR deficiency, confirming the centrality of this axis. These findings define an unrecognized EGFR-MAPK14-CEBPβ-PGLYRP1-TREM1 circuit that links receptor signaling to pathological NETosis and highlight a promising therapeutic target to attenuate neutrophil-driven immunopathology in sepsis.