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Involvement of ACSL3 in the formation of autophagosomes and lipid droplets during
starvation conditions
#MMPMID41346954
Kato S
; Tagaya M
Autophagy Rep
2025[]; 4
(1
): 2593061
PMID41346954
show ga
Acyl-CoA synthetase long-chain (ACSL) catalyzes the conversion of fatty acids
into acyl-CoA, which is used for neutral lipid and phospholipid synthesis.
Previous studies revealed that yeast Faa1 and mammalian ACSL4 play a crucial role
in phagophore expansion by locally synthesizing phospholipids. We found that
another member of ACSL protein family, ACSL3, which is involved in lipid droplet
biogenesis under energy-rich conditions and is regulated by SYNTAXIN17, also
participates in autophagosome formation, but in a different manner. Knockdown of
ACSL3 suppressed punctum formation of early autophagosomal marker proteins such
as FIP200 and WIPI2 in starved cells, generating nonfunctional multi-membrane
autophagosome-like structures. In contrast, ACSL4 suppression blocked
autophagosome formation without affecting punctum formation of early
autophagosomal marker proteins. Mechanistic analysis revealed that ACSL3
functions independently of its enzymatic activity, while catalytic activity of
ACSL4 is required for autophagosome formation as well as LC3 (known as MAP1LC3
proteins) protein lipidation. Furthermore, ACSL3 has been shown to be essential
for lipid droplet biogenesis during starvation. These findings establish ACSL3 as
a key player in two events in early autophagy: formation of autophagosomes and
lipid droplets.
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