GAN (gigaxonin) E3 ligase and ATG16L1: master and commander of autophagosome production

ABSTRACT

The sequential action of ATG proteins guarantees the formation of the autophagosome from the steps of the induction, nucleation, elongation and sealing of the phagophore membrane. Posttranslational modifications further add to the fine-tuning regulation of this highly ordered machinery and confer, in space and time, the dynamics necessary to respond to macroautophagy/autophagy activation, and to shut it down. Recently, we reported the discovery of GAN (gigaxonin), an E3 ubiquitin ligase adaptor as a key regulator of the elongation step of phagophore formation. GAN interacts, ubiquitinates and degrades ATG16L1, which forms a complex with the ATG12–ATG5 ubiquitin-like conjugation system, and specifies the site of lipidation of LC3 by this complex onto the nascent phagophore. Accordingly, depletion of GAN in primary neurons causes the accumulation of ATG16L1 and decreases the autophagy flux by impairing the net production of autophagosomes. Considering the pivotal role of ATG16L1 in autophagy, and the reversal of the deficits upon reintroduction of GAN, one can speculate that GAN constitutes a novel molecular switch to fine tune the autophagy machinery.

KEYWORDS:

• ATG16L1
• autophagosome production
• E3 ligase
• GAN/gigaxonin
• ubiquitin-mediated degradation

Disclosure statement

No potential conflict of interest was reported by the author.

Additional information

Funding

PB’s laboratory was funded by INSERM (ATIP-Avenir program), The Région Languedoc Roussillon (Chercheuse d’Avenir program) and the Association Française contre les Myopathies (AFM).