Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Rab GTPases are switched from their GDP-bound inactive conformation to a GTP-bound active state by guanine nucleotide exchange factors (GEFs). The first putative GEFs isolated for Rabs are
RABIF
(Rab-interacting factor)/MSS4 (mammalian suppressor of Sec4) and its yeast homolog DSS4 (dominant suppressor of Sec4). However, the biological function and molecular mechanism of these molecules remained unclear. In a genome-wide CRISPR genetic screen, we isolated
RABIF
as a positive regulator of exocytosis. Knockout of
RABIF
severely impaired insulin-stimulated GLUT4 exocytosis in adipocytes. Unexpectedly, we discovered that
RABIF
does not function as a GEF, as previously assumed. Instead,
RABIF
promotes the stability of Rab10, a key Rab in GLUT4 exocytosis. In the absence of
RABIF
, Rab10 can be efficiently synthesized but is rapidly degraded by the
proteasome
, leading to exocytosis defects. Strikingly, restoration of Rab10 expression rescues exocytosis defects, bypassing the requirement for
RABIF
. These findings reveal a crucial role of
RABIF
in vesicle transport and establish
RABIF
as a Rab-stabilizing holdase chaperone, a previously unrecognized mode of Rab regulation independent of its GDP-releasing activity. Besides Rab10,
RABIF
also regulates the stability of two other Rab GTPases, Rab8 and Rab13, suggesting that the requirement of holdase chaperones is likely a general feature of Rab GTPases.
...
PMID:RABIF/MSS4 is a Rab-stabilizing holdase chaperone required for GLUT4 exocytosis. 2889 7
