Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.
Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, NY, USA.
Nat Commun. 2024 Nov 28;15(1):10364. doi: 10.1038/s41467-024-54749-2.
Cell death plasticity is crucial for modulating tissue homeostasis and immune responses, but our understanding of the molecular components that regulate cell death pathways to determine cell fate remains limited. Here, a CRISPR screen of acute myeloid leukemia cells identifies protein tyrosine phosphatase non-receptor type 23 (PTPN23) as essential for survival. Loss of PTPN23 activates nuclear factor-kappa B, apoptotic, necroptotic, and pyroptotic pathways by causing the accumulation of death receptors and toll-like receptors (TLRs) in endosomes. These effects are recapitulated by depletion of PTPN23 co-dependent genes in the endosomal sorting complex required for transport (ESCRT) pathway. Through proximity-dependent biotin labeling, we show that NAK-associated protein 1 interacts with PTPN23 to facilitate endosomal sorting of tumor necrosis factor receptor 1 (TNFR1), sensitizing cells to TNF-α-induced cytotoxicity. Our findings reveal PTPN23-dependent ESCRT machinery as a cell death checkpoint that regulates the spatiotemporal distribution of death receptors and TLRs to restrain multiple cell death pathways.
细胞死亡的可塑性对于调节组织稳态和免疫反应至关重要，但我们对于调控细胞死亡途径以决定细胞命运的分子组成的理解仍然有限。在这里，通过对急性髓系白血病细胞进行 CRISPR 筛选，我们确定蛋白酪氨酸磷酸酶非受体型 23（PTPN23）是存活所必需的。PTPN23 的缺失通过在内体中积累死亡受体和 Toll 样受体（TLRs），激活核因子-κB、凋亡、坏死和焦亡途径。ESCRT 途径中 PTPN23 共依赖基因的缺失可以重现这些效应。通过邻近依赖性生物素标记，我们表明 NAK 相关蛋白 1 与 PTPN23 相互作用，促进肿瘤坏死因子受体 1（TNFR1）在内体中的分拣，使细胞对 TNF-α 诱导的细胞毒性敏感。我们的发现揭示了依赖 PTPN23 的 ESCRT 机制作为细胞死亡检查点，调节死亡受体和 TLR 的时空分布，以限制多种细胞死亡途径。
