Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
Center for Regenerative Medicine, Heart Institute, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, 560 Channelside Drive, MDD714, Tampa, FL, 33602, USA.
Cell Death Differ. 2024 Jan;31(1):40-52. doi: 10.1038/s41418-023-01237-7. Epub 2023 Nov 23.
Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is not clear. We have determined that activated MLKL translocates to the lysosomal membrane during necroptosis induction. The subsequent polymerization of MLKL induces lysosome clustering and fusion and eventual lysosomal membrane permeabilization (LMP). This LMP leads to the rapid release of lysosomal contents into the cytosol, resulting in a massive surge in cathepsin levels, with Cathepsin B (CTSB) as a significant contributor to the ensuing cell death as it cleaves many proteins essential for cell survival. Importantly, chemical inhibition or knockdown of CTSB protects cells from necroptosis. Furthermore, induced polymerization of the MLKL N-terminal domain (NTD) also triggers LMP, leading to CTSB release and subsequent cell death. These findings clearly establish the critical role of MLKL polymerization induced lysosomal membrane permeabilization (MPI-LMP) in the process of necroptosis.
混合谱系激酶样蛋白（MLKL）形成淀粉样聚合物以促进坏死性凋亡；然而，这些聚合物引发细胞死亡的机制尚不清楚。我们已经确定，在坏死性凋亡诱导过程中，激活的 MLKL 易位到溶酶体膜上。随后 MLKL 的聚合诱导溶酶体聚集和融合，最终导致溶酶体膜通透性（LMP）。这种 LMP 导致溶酶体内容物迅速释放到细胞质中，导致组织蛋白酶水平的大量激增，其中组织蛋白酶 B（CTSB）是导致随后细胞死亡的重要因素，因为它切割许多对细胞存活至关重要的蛋白质。重要的是，CTSB 的化学抑制或敲低可保护细胞免受坏死性凋亡。此外，MLKL N 端结构域（NTD）的诱导聚合也会引发 LMP，导致 CTSB 释放和随后的细胞死亡。这些发现清楚地确立了 MLKL 聚合诱导的溶酶体膜通透性（MPI-LMP）在坏死性凋亡过程中的关键作用。
