TY  - JOUR
A1  - Herhaus, Lina
A1  - Bhaskara, Ramachandra M.
A1  - Lystad, Alf Håkon
A1  - Gestal-Mato, Uxía
A1  - Covarrubias-Pinto, Adriana
A1  - Bonn, Florian
A1  - Simonsen, Anne
A1  - Hummer, Gerhard
A1  - Đikić, Ivan
T1  - TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease
T2  - EMBO reports
N2  - 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.
KW  - ATG4
KW  - ATG8
KW  - autophagy
KW  - phosphorylation
KW  - TBK1
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63815
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-638159
SN  - 1469-3178
N1  - This work was supported by grants from the DFG (SFB 1177 on selective autophagy), the Cluster of Excellence “Macromolecular Complexes” of the Goethe University Frankfurt (EXC 115). L.H. is supported by a European Molecular Biology Organization (EMBO) long-term postdoctoral fellowship (ALTF 1200-2014, LTFCOFUND2013, GA-2013-609409). R.M.B. and G.H. acknowledge support by the Max Planck Society and computational resources at MPCDF, Garching. A.H.L. and A.S. were supported by the Research Council of Norway (project number 221831) and through its Centers of Excellence funding scheme (project number 262652), as well as the Norwegian Cancer Society (project number 171318).
VL  - 21
IS  - 1, art. e48317
SP  - 1
EP  - 20
PB  - EMBO Press
CY  - Heidelberg
ER  -