Phosphorylation-Coupled Autoregulation Maintains Functional ER Exit Sites

Secretory proteins are synthesized in the endoplasmic reticulum (ER) and begin their transport from specialized domains on the ER called ER exit sites (ERES). We previously demonstrated that the interaction between TANGO1 and Sec16 is critical for ERES formation. In this study, we reveal that the phosphorylation of TANGO1 and Sec16 is regulated by a FAM83A/CK1α-mediated negative feedback loop. Conversely, their dephosphorylation is regulated in a spatially distinct manner by different phosphatase complexes: PPP6R3/PPP6C for Sec16 and PPP1R15B/PPP1C for TANGO1. Excessive phosphorylation of either TANGO1 or Sec16 leads to ERES disassembly, while excessive dephosphorylation impairs secretion. Our findings demonstrate that maintaining a balanced phosphorylation state of TANGO1 and Sec16 through autoregulation by FAM83A/CK1α and the phosphatases PP1 and PP6 is essential for sustaining proper secretory activity at the ERES.