Phosphorylation of SNX27 by MAPK11/14 links cellular stress-signaling pathways with endocytic recycling

Endocytosed proteins can be delivered to lysosomes for degradation or recycled to either the trans-Golgi network or the plasma membrane. It remains poorly understood how the recycling versus degradation of cargoes is determined. Here, we show that multiple extracellular stimuli, including starvation, LPS, IL-6, and EGF treatment, can strongly inhibit endocytic recycling of multiple cargoes through the activation of MAPK11/14. The stress-induced kinases in turn directly phosphorylate SNX27, a key regulator of endocytic recycling, at serine 51 (Ser51). Phosphorylation of SNX27 at Ser51 alters the conformation of its cargo-binding pocket and decreases the interaction between SNX27 and cargo proteins, thereby inhibiting endocytic recycling. Our study indicates that endocytic recycling is highly dynamic and can crosstalk with cellular stress-signaling pathways. Suppression of endocytic recycling and enhancement of receptor lysosomal degradation serve as new mechanisms for cells to cope with stress and save energy.

Automated summary

This study reveals that external stimuli such as starvation, LPS, and inflammatory cytokines can inhibit endocytic recycling of proteins by activating MAPK11/14, leading to a disruption in the balance between recycling and degradation. Stress-induced kinases phosphorylate SNX27 at Ser51, altering its binding with cargo proteins and thereby suppressing endocytic recycling. The findings suggest that cells can modulate endocytic recycling in response to stress signals, providing new insights into how cells cope with stress and conserve energy.