The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1, which encodes p62, are linked to hereditary inflammatory conditions such as Paget’s disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62^TRM. We found that p62^TRM, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapamycin complex 1 (mTORC1). The kinase RIPK1 and caspase-8 controlled p62^TRM production and thus promoted mTORC1 signaling. An FTD-linked p62 D329G polymorphism and a rare D329H variant could not be proteolyzed by caspase-8, and these noncleavable variants failed to activate mTORC1, thereby revealing the detrimental effect of these mutations. These findings on the role of p62^TRM provide new insights into SQSTM1-linked diseases and mTORC1 signaling.

多结构域支架蛋白 p62（也称为 sequestosome-1）参与自噬、抗菌免疫和肿瘤发生。编码 p62 的SQSTM1中的突变与遗传性炎症有关，例如骨佩吉特病、额颞叶痴呆 (FTD)、肌萎缩侧索硬化和带有边缘空泡的远端肌病。在这里，我们报告了 p62 被蛋白酶 caspase-8 蛋白水解修剪成一种稳定的蛋白质，我们称之为 p62 ^TRM。我们发现 p62 ^TRM而非全长 p62 通过雷帕霉素复合物 1 (mTORC1) 的机制靶标参与营养感应和体内平衡。激酶 RIPK1 和 caspase-8 控制 p62 ^TRM生产，从而促进mTORC1信号。FTD 相关的 p62 D329G 多态性和罕见的 D329H 变体不能被 caspase-8 蛋白水解，并且这些不可切割的变体未能激活 mTORC1，从而揭示了这些突变的有害影响。这些关于 p62 ^{TRM作用的发现为}SQSTM1 相关疾病和 mTORC1 信号传导提供了新的见解。