Role of USP19 in unconventional secretion of misfolded proteins

为了保障蛋白质组的完整性，细胞依赖蛋白酶体降解异常多肽，依靠溶酶体降解大的不溶性蛋白质聚集体。然而，目前尚不清楚细胞如何去除由于蛋白酶体不足或溶酶体功能障碍而逃脱降解的缺陷蛋白质。通过研究USP19的功能，我们发现了一种称为错误折叠相关蛋白分泌的途径。这一过程使用USP19优先输出异常的胞浆蛋白。有趣的是，USP19的催化结构域具有前所未有的伴侣活性，允许错误折叠的蛋白质重新聚集到内质网表面进行脱泛素化。去泛素化的货物被包裹到内质网相关的晚期内体中，并分泌到细胞外部。USP19基因缺失的细胞不能有效地分泌不需要的蛋白质，在蛋白酶体抑制剂的作用下，细胞的生长速度比野生型细胞慢。总之，我们的发现描绘了一条蛋白质质量控制(PQC)途径，与基于降解的PQC机制不同，该途径通过非传统的蛋白质分泌过程输出错误折叠的蛋白质来促进蛋白质动态平衡。

To safeguard the proteomic integrity, cells rely on the proteasome to degrade aberrant polypeptides and the lysosomes to degrade large insoluble protein aggregates. However, it is unclear how cells remove defective proteins that have escaped degradation owing to proteasome insufficiency or dysfunction in the lysosome. By study the function of USP19, an endoplamsic reticulum-associated deubiquitinase, we have uncovered a pathway termed misfolding-associated protein secretion. This process uses USP19 to preferentially export aberrant cytosolic proteins. Intriguingly, the catalytic domain of USP19 possesses an unprecedented chaperone activity, allowing recruitment of misfolded proteins to the ER surface for deubiquitylation. Deubiquitylated cargos are encapsulated into ER-associated late endosomes and secreted to the cell exterior. USP19-deficient cells cannot efficiently secrete unwanted proteins and grow more slowly than wild-type cells on exposure to a proteasome inhibitor. Together, our findings delineate a protein quality control (PQC) pathway, which, unlike degradation-based PQC mechanisms, promotes protein homeostasis by exporting misfolded proteins through an unconventional protein secretion process.