The Cys/N-degron pathway mediates secretory autophagy under oxidative stress

Leaderless cytokines lacking signal peptides are dominantly secreted as first-line responses to cellular stresses. However, the molecular mechanisms governing their secretion remain murky. Here, we report that leaderless cytokines are released by secretory autophagy, whose amphisome biogenesis is mediated by the Cys/N-degron pathway during oxidative stress. The Nt-Cysox degron of cytokines undergoes ATE1-dependent Nt-arginylation and binds the ZZ domain of the autophagic cargo receptor/N-recognin p62/SQSTM1. Such interaction conformationally and biologically activates p62 into oligomeric complexes with the multivesicular body (MVB) transmembrane protein CD63, whose topology inversion mediates phagophore-MVB fusion for amphisome biogenesis. Peptidomimetic p62 antagonists were developed to inhibit secretory autophagy of pro-inflammatory cytokines in models of chronic obstructive pulmonary disease (COPD). Our results implicate the Cys/N-degron pathway in amphisome biogenesis for paracrine inflammatory signaling.