Work

Phosphorylation-coupled autoregulation of TANGO1 and Sec16A maintains functional ER exit sites

Year: 2025

Type: article

Abstract: Secretory proteins are synthesized in the endoplasmic reticulum (ER) and begin their transport from specialized domains on the ER called ER exit sites (ERES), where COPII proteins assemble. We previously demonstrated that the interaction between TANGO1 and Sec16A is critical for ERES formation. In this study, we reveal that the phosphorylation of TANGO1 and Sec16A 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 Sec16A and PPP1R15B/PPP1C for TANGO1. Excessive phosphorylation of either TANGO1 or Sec16A leads to ERES disassembly, while excessive dephosphorylation impairs secretion. Our findings demonstrate that maintaining a balanced phosphorylation state of TANGO1 and Sec16A through autoregulation by FAM83A/CK1α and the phosphatases PP1 and PP6 is essential for sustaining proper secretory activity at the ERES. The ER exit site is a portal on the endoplasmic reticulum where secretory proteins depart. Here, the authors revealed that a balanced phosphorylation state of the ER exit site proteins TANGO1 and Sec16A, maintained by kinase–phosphatase feedback loops, is crucial for secretion.

Source: Nature Communications

DOI: 10.1038/s41467-025-65409-4

Authors: Miharu Maeda, Masashi Arakawa, Masaki Wakabayashi, Yukie Komatsu, Kota Saito

Institutions: National Cerebral and Cardiovascular Center, Akita University

Language: English

Topic: Cellular transport and secretion

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,990