Metabolic-Stress-Induced Rearrangement of the 14-3-3ζ Interactome Promotes Autophagy via a ULK1- and AMPK-Regulated 14-3-3ζ Interaction with Phosphorylated Atg9

Abstract

c 14-3-3 promotes cell survival via dynamic interactions with a vast network of binding partners, many of which are involved in stress regulation. We show here that hypoxia (low glucose and oxygen) triggers a rearrangement of the 14-3-3 interactome to favor an interaction with the core autophagy regulator Atg9A. Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3 docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. However, upon induction of hypoxic stress, activated AMPK bypasses the requirement for ULK1 and mediates S761 phosphorylation directly, resulting in an increase in 14-3-3 interactions, recruitment of Atg9A to LC3-positive autophagosomes, and enhanced autophagosome production. These data suggest a novel mechanism whereby the level of autophagy induction can be modulated by AMPK/ULK1-mediated phosphorylation of mammalian Atg9A.

Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection

“…AMPKα phosphorylation of ULK1 also controls Atg9a localization (Mack et al, 2012). In fact, the localization of Atg9a to autophagosomes requires ULK1- and AMPK-dependent phosphorylation of this protein (Weerasekara et al, 2014). Despite these advances, precise roles of AIC components in regulating infection remain to be elucidated.…”

Analysis of the native conformation of the LIR/AIM motif in the Atg8/LC3/GABARAP-binding proteins

“…machinery when they revealed that the YWHA/14-3-3 docking sites are created by phosphorylation on Ser234 and Ser295 in human BECN1 22 and on Ser761 near the C terminus of mammalian ATG9. 23 These docking sites are also associated with structurally plastic protein domains (Fig. S3).…”

The AMP-Related Kinase (AMPK) Induces Ca 2+ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

“…This displacement of cofilin from 14-3-3 clearly involves AMPK because the effect was abolished after silencing of AMPK. Interestingly enough, AMPK has been shown to phosphorylate several 14-3-3 binding partners [56][57][58] consistent with a competitive displacement of cofilin. Free cofilin is not anymore protected from dephosphorylation and can subsequently be dephosphorylated, 59 leading to cofilin activation and, ultimately, actin filament severing.…”