TBK1‐mediated phosphorylation of LC3C and GABARAP‐L2 controls autophagosome shedding by ATG4 protease. (11th November 2019)

• Record Type: Journal Article
• Authors: Herhaus, Lina; Bhaskara, Ramachandra M; Lystad, Alf Håkon; Gestal‐Mato, Uxía; Covarrubias‐Pinto, Adriana; Bonn, Florian; Simonsen, Anne; Hummer, Gerhard; Dikic, Ivan
• Is Part Of: EMBO reports. Volume 21:Number 1(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-11-11
• Subjects: ATG4 -- ATG8 -- autophagy -- phosphorylation -- TBK1; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201948317
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Autophagy is a highly conserved catabolic process through which defective or otherwise harmful cellular components are targeted for degradation via the lysosomal route. Regulatory pathways, involving post‐translational modifications such as phosphorylation, play a critical role in controlling this tightly orchestrated process. Here, we demonstrate that TBK1 regulates autophagy by phosphorylating autophagy modifiers LC3C and GABARAP‐L2 on surface‐exposed serine residues (LC3C S93 and S96; GABARAP‐L2 S87 and S88). This phosphorylation event impedes their binding to the processing enzyme ATG4 by destabilizing the complex. Phosphorylated LC3C/GABARAP‐L2 cannot be removed from liposomes by ATG4 and are thus protected from ATG4‐mediated premature removal from nascent autophagosomes. This ensures a steady coat of lipidated LC3C/GABARAP‐L2 throughout the early steps in autophagosome formation and aids in maintaining a unidirectional flow of the autophagosome to the lysosome. Taken together, we present a new regulatory mechanism of autophagy, which influences the conjugation and de‐conjugation of LC3C and GABARAP‐L2 to autophagosomes by TBK1‐mediated phosphorylation. Synopsis: LC3C and GABARAP‐L2 processing by ATG4 is controlled by TBK1‐mediated phosphorylation. This regulatory mechanism prevents premature shedding of LC3C and GABARAP‐L2 from autophagosomes. TBK1 phosphorylates autophagy modifiers LC3C and GABARAP‐L2 on surface‐exposed serine‐residues. GABARAP‐L2 S87/88‐PO4 and LC3C S93/96‐PO4 impedes binding to the ATG4 protease. Phosphorylated LC3C/GABARAP‐L2 are protected from ATG4‐mediated premature removal from autophagosomes. Abstract : LC3C and GABARAP‐L2 processing by ATG4 is controlled by TBK1‐mediated phosphorylation. This regulatory mechanism prevents premature shedding of LC3C and GABARAP‐L2 from autophagosomes.