Cell Death and Differentiation最新文献

Transforming growth factor (TGF)-β signaling is a key driver to induce epithelial-to-mesenchymal transition (EMT), a process that enhances cancer cell plasticity and metastatic potential. However, the role of circular RNAs (circRNAs) in TGF-β signaling remains largely unexplored. Here, we identify circTGFBR2(3-6), a circRNA derived from TGF-β receptor 2 (TGFBR2) pre-mRNA, as a critical enhancer of TGF-β/SMAD signaling in breast cancer cells. Depletion of circTGFBR2(3-6) inhibits TGF-β-induced EMT, cell migration, and in vivo extravasation of breast cancer cells. Mechanistically, circTGFBR2(3-6) acts as a scaffold that facilitates the interaction between the RNA-binding protein insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and TGF-β receptor 1 (TGFBR1) mRNA in an N⁶-methyladenosine (m⁶A)-dependent manner, and thereby stabilizes TGFBR1 mRNA and promotes its expression. Furthermore, IGF2BP3 knockdown reduces circTGFBR2(3-6)-mediated enhancement of TGF-β/SMAD signaling, as well as TGF-β-induced EMT and cell migration. Our findings identify circTGFBR2(3-6) as a novel potentiator of TGF-β/SMAD signaling at the receptor level and highlight IGF2BP3 as a critical m⁶A reader that mediates circTGFBR2(3-6)-driven breast cancer cell plasticity.

Osteoclasts are essential for bone remodeling; however, their hyperactivity leads to pathological bone loss. While inflammasome-activated caspases are known to influence osteoclastogenesis, the role of caspase-11, beyond its conventional function in pyroptosis, remains unclear. Here, we identified caspase-11 as a pivotal regulator of RANKL-induced osteoclast differentiation. Caspase-11 expression and activity were elevated in bone tissues exhibiting excessive resorption and in RANKL-stimulated bone marrow-derived macrophages. Unlike inflammasome activation, RANKL-induced caspase-11 did not trigger typical inflammasome-associated inflammatory responses. Caspase-11 knockout mice displayed increased bone mass and resistance to RANKL-induced bone resorption; in parallel, genetic or pharmacological inhibition of caspase-11 impaired osteoclast differentiation in vitro. Notably, mechanistic studies revealed that RANKL-activated caspase-11 translocates to the nucleus, where it cleaves and inactivates poly(ADP-ribose) polymerase 1 (PARP1), a transcriptional repressor of osteoclastogenesis. In addition, using the caspase-11 inhibitor, VX-765, substantially reduced ovariectomy-induced bone loss. These findings collectively reveal a novel, non-inflammatory function of caspase-11 in osteoclastogenesis, positioning it as a promising therapeutic target for osteolytic diseases.

Ubiquitin removal by deubiquitinating enzymes (DUBs) is a crucial cellular process. Among the DUBs, ubiquitin-specific protease 13 (USP13) is overexpressed in multiple cancers and is associated with tumorigenesis and poor prognosis. However, its involvement in the cell death pathway is poorly understood. Thus, we describe the novel function of USP13 as a crucial regulator of necroptosis. USP13 interacts with cellular IAP2 (cIAP2), stabilizing cIAP2 proteins in colorectal cancer (CRC) cells. The TCGA-COAD and GEO databases revealed USP13 upregulation in CRC patients and its association with poor clinical outcomes. The loss of USP13 significantly potentiates TNF-α/SMAC mimetic birinapant/pan-caspase inhibitor Z-VAD-FMK (TBZ)-induced necroptosis in CRC cells and diminishes tumor growth in a xenograft model. Thereby, USP13 may serve as a potential therapeutic target for anticancer treatment of CRC.

Regulated cell death is integral to sculpting the developing brain, yet the relative contributions of extrinsic apoptosis and necroptosis remain unclear. Here, we leverage single-cell mass cytometry (CyTOF) to characterize the cellular landscape of the mouse telencephalon in wild-type (WT), RIPK3 knockout (RIPK3 KO), and RIPK3/Caspase-8 double knockout (DKO) mice. Strikingly, combined deletion of RIPK3 and Caspase-8 leads to a 12.6% increase in total cell count, challenging the prevailing notion that intrinsic apoptosis exclusively governs developmental cell elimination. Detailed subpopulation analysis reveals that DKO mice display selective enrichment of Tbr2⁺ intermediate progenitors and endothelial cells, underscoring distinct, cell type-specific roles for extrinsic apoptotic and necroptotic pathways. These findings provide a revised framework for understanding the coordinated regulation of cell number during telencephalic development and suggest potential mechanistic links to neurodevelopmental disorders characterized by aberrant cell death.