Atg8 family LC3/GABARAP proteins are crucial for autophagosome–lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation

Abstract

Current autophagy models suggest that Atg8 family LC3/GABARAP proteins are essential mediators of autophagosome biogenesis. Nguyen et al. exploit CRISPR/Cas9-generated knockouts of the LC3 or GABARAP subfamilies, or both subfamilies, to show that Atg8s are dispensable for autophagosome biogenesis but essential for autophagosome–lysosome fusion.

Macroautophagy without LC3 conjugation?

“…This may explain, at least in part, some of the phenotypic differences and severities existing among different autophagy KO mouse models, depending whether they affect ATG8 conjugation or affect alternative or earlier steps of the process [10][11][12]. It is interesting to contrast and compare the data reported in this research article to a very recent study in cells lacking all ATG8 family members, where autophagosome-lysosome fusion appears to be compromised [13]. Figure), autophagosome-like structures can still form and acquire STX17.…”

New insights into autophagosome–lysosome fusion

“…In addition to its role in autophagosome maturation, the ATG conjugation system (consisting of ATG3, ATG5 and ATG7) has been recently shown to be required for efficient degradation of the inner autophagic membrane; however, it is not required for autophagosomelysosome fusion, although the rate of autophagosome formation is reduced to ∼30% in ATG conjugation-deficient cells (Tsuboyama et al, 2016). By contrast, another study that was using cell lines in which the entire ATG8 protein family had been knocked out revealed that LC3 and GABARAP proteins are not required for autophagosome formation, but are crucial for autophagosomelysosome fusion (Nguyen et al, 2016). The lack of fusion is probably due to the impaired recruitment of the adaptor protein PLEKHM1 (McEwan et al, 2015) (see also below) to autophagosomes.…”

“…However, the exact role of PI4P in the fusion process needs to be clarified in future studies. In line with the function of GABARAP during autophagosome-lysosome fusion, a recent systematic functional analysis of the Atg8 family in mammals revealed that the GABARAP subfamily promotes recruitment of PLEKHM1 and governs autophagosome-lysosome fusion, whereas the LC3 subfamily has a less prominent role in these particular processes (Nguyen et al, 2016).…”

PINK1 and Parkin: emerging themes in mitochondrial homeostasis

“…Until recently, it was widely assumed that the ATG-conjugation machinery is crucial for autophagosome biogenesis and cargo incorporation. A new study has cast doubt on this, suggesting that while LC3 is essential for autophagosome-endolysosome fusion, it is dispensable for the autophagic encapsulation of damaged mitochondria [24]. Consistent with a role outside of autophagosome biogenesis, other recent observations indicate LC3 conjugation is instead required to orchestrate the degradation of the inner autolysosomal membrane following autophagosome-lysosome fusion [25].…”