Sec16 in conventional and unconventional exocytosis: Working at the interface of membrane traffic and secretory autophagy?

Sec16 is classically perceived to be a scaffolding protein localized to the transitional endoplasmic reticulum (tER) or the ER exit sites (ERES), and has a conserved function in facilitating coat protein II (COPII) complex‐mediated ER exit. Recent findings have, however, pointed toward a role for Sec16 in unconventional exocytosis of certain membrane proteins, such as the Cystic fibrosis transmembrane conductance regulator (CFTR) in mammalian cells, and possibly also α‐integrin in certain contexts of Drosophila development. In this regard, Sec16 interacts with components of a recently deciphered pathway of stress‐induced unconventional exocytosis, which is dependent on the tether protein Golgi reassembly stacking proteins (GRASPs) and the autophagy pathway. Intriguingly, Sec16 also appears to be post‐translationally modified by autophagy‐related signaling processes. Sec16 is known to be phosphorylated by the atypical extracellular signal regulated kinase 7 (Erk7) upon serum and amino acid starvation, both represent conditions that trigger autophagy. Recent work has also shown that Sec16 is phosphorylated, and thus regulated by the prominent autophagy‐initiating Unc‐51‐like autophagy activating kinase 1 (Ulk1), as well as another autophagy modulator Leucine‐rich repeat kinase 2 (Lrrk2). The picture emerging from Sec16's network of physical and functional interactors allows the speculation that Sec16 is situated (and may in yet undefined ways function) at the interface between COPII‐mediated exocytosis of conventional vesicular traffic and the GRASP/autophagy‐dependent mode of unconventional exocytosis.