Lck regulates T cell activation through phosphorylation of p62.

Autophagy is crucial for T cell activation, yet how T cell receptor (TCR) signaling regulates autophagy is largely unknown. The autophagy receptor p62 was first identified as a lymphocyte-specific protein tyrosine kinase (Lck) SH2 domain ligand. However, the functional significance of the Lck-p62 association in T cells remains unclear. Here, we demonstrate that Lck inhibits TCR-induced autophagy via phosphorylating p62, thereby promoting T cell activation. Upon TCR stimulation, Lck transiently phosphorylates p62 at tyrosine 433 (Y433), peaking at 5 min and declining by 15 min. The p62-Y433F mutant displays enhanced TCR-induced association with LC3 and ULK1 complex components, thereby promoting autophagy. Consequently, this mutant suppresses TCR-induced NF-κB activation and IL-2 production by strengthening its interaction with Bcl10 and accelerating the autophagic clearance of Bcl10. Together, we demonstrate that the transient phosphorylation of p62 by Lck facilitates p62 transition between adapting Bcl10-NF-κB signaling and promoting Bcl10 autophagic degradation, revealing a temporal cooperation between TCR signaling and autophagy that occurs during the early phase of TCR stimulation.