FUN14 domain-containing protein 1
Domain
The YXXL motif mediates the interaction with MAP1 LC3 family proteins MAP1LC3A, MAP1LC3B and GABARAP.
Function
Integral mitochondrial outer-membrane protein that mediates the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) (PubMed:33972548). In turn, mediates angiogenesis and neoangiogenesis through interference with intracellular Ca(2+) communication and regulation of the vascular endothelial growth factor receptor KDR/VEGFR2 expression at both mRNA and protein levels (PubMed:33972548). Acts also as an activator of hypoxia-induced mitophagy, an important mechanism for mitochondrial quality and homeostasis, by interacting with and recruiting LC3 protein family to mitochondria (PubMed:22267086, PubMed:24671035, PubMed:24746696, PubMed:27653272). Mechanistically, recruits DRP1 at ER-mitochondria contact sites leading to DRP1 oligomerization and GTPase activity to facilitate mitochondrial fission during hypoxia (PubMed:27145933, PubMed:33978709). Additionally, plays a role in hepatic ferroptosis by interacting directly with glutathione peroxidase/GPX4 to facilitate its recruitment into mitochondria through TOM/TIM complex where it is degraded by mitophagy (PubMed:36828120).
Post-translational modifications
Phosphorylation at Ser-13 by CK2 and at Tyr-18 by SRC inhibits activation of mitophagy. Following hypoxia, dephosphorylated at Tyr-18, leading to interaction with MAP1 LC3 family proteins and triggering mitophagy. Dephosphorylation is mediated by PGAM5 (PubMed:24746696). Phosphorylated by ULK1 at Ser-17 which enhances FUNDC1 binding to LC3 (PubMed:24671035).
Ubiquitinated on Lys-119. Deubiquitinated by USP19; leading to hypoxia-induced DRP1 oligomerization and GTPase activity.
Sequence Similarities
Belongs to the FUN14 family.
Tissue Specificity
Widely expressed.
Cellular localization
- Mitochondrion outer membrane
- Multi-pass membrane protein
Alternative names
FUN14 domain-containing protein 1, FUNDC1