Regulating peroxisome-ER contacts via the ACBD5-VAPB tether by FFAT motif phosphorylation and GSK3β
Journal of Cell Biology(2021)
摘要
Peroxisomes and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism. They form membrane contacts through interaction of the peroxisomal membrane protein ACBD5 [acyl-coenzyme A-binding domain protein 5] and the ER-resident protein VAPB [vesicle-associated membrane protein-associated protein B]. ACBD5 binds to the major sperm protein domain of VAPB via its FFAT-like [two phenylalanines (FF) in an acidic tract] motif. However, molecular mechanisms, which regulate formation of these membrane contact sites, are unknown. Here, we reveal that peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation. We show that ACBD5-VAPB binding is phosphatase-sensitive and identify phosphorylation sites in the flanking regions and core of the FFAT-like motif, which alter interaction with VAPB and thus, peroxisome-ER contact sites differently. Moreover, we demonstrate that GSK3β [glycogen synthase kinase-3 beta] regulates this interaction. Our findings reveal for the first time a molecular mechanism for the regulation of peroxisome-ER contacts in mammalian cells and expand the current model of FFAT motifs and VAP interaction.
SUMMARY Kors et al. reveal that peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation and GSK3β in mammalian cells. Phosphorylation sites in the FFAT-like motif of ACBD5 affect the binding to VAPB and thus, peroxisome-ER contact sites, differently.
### Competing Interest Statement
The authors have declared no competing interest.
* ACBD
: acyl-coenzyme A-binding domain containing protein
ER
: endoplasmic reticulum
FFAT
: two phenylalanines (FF) in an acidic tract
λPP
: λ protein phosphatase
GSK3β
: glycogen synthase kinase-3 beta
IP
: immunoprecipitation
MS
: mass spectrometry
MSP
: major sperm protein
VAP
: vesicle-associated membrane protein (VAMP)-associated protein
VLCFA
: very long-chain fatty acid.
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