Endosomal stress, a newly defined organelle stress, induces inflammation via ubiquitin signaling

Endosome is an essential organelle located at the center of membrane traffic and mainly sorts plasma membrane proteins internalized by endocytosis in cooperation with ubiquitination, especially lysine-63-linked polyubiquitin chains (K63 ubiquitin chains). Briefly, ubiquitinated proteins on early endosomes are sequentially recognized by ESCRT complexes (endosomal sorting complexes required for transport-0, -Ⅰ, -Ⅱ, and -Ⅲ) and delivered to late endosomes/lysosomes where they are degraded by acid hydrolases.

Prolonged defects in the endosomal machinery lead to cell death, but the major effects on cellular signaling were poorly understood. To address this knowledge gap, we first considered the abnormal accumulation of K63 ubiquitin chains on defective endosomes as “endosomal stress”, an organelle stress, and investigated the cellular responses to endosomal stress caused by depletion of USP8, an essential endosomal deubiquitinase.

First, our proteomic screening revealed that endosomal stress caused by USP8 depletion induces an immune response. Further analysis showed that decoders for K63 ubiquitin chains, such as TAB2/3 and p62, were recruited to endosomes, and consequently activated NF-kB- and Nrf2-mediated gene expression. Upregulated chemokines such as CCL5 were sufficient to transmit the signals to neighboring cells. Furthermore, we found that oxidative stress, an environmental stimulus that potentially suppresses USP8 activity, induced endosomal stress.

Collectively, our results demonstrate that endosomal stress triggers inflammation and that USP8 is a gatekeeper of misdirected ubiquitin signals and inhibits immune and stress response pathways by removing K63-linked ubiquitin chains from endosomes. In this context, our findings may exemplify the redecoding of K63 ubiquitin chains from membrane trafficking to signal transduction by switching decoder proteins. Our achievement hopefully contributes to the study of organelle stress and ubiquitin-mediated regulation and prompts us to seek the physiology and clinical relevance of endosomal stress.