Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement.
Cul3, a Cullin family scaffold protein, is thought to mediate the assembly of a large number of SCF (Skp1-Cullin1-F-box protein)-like ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors. Cul3 controls early embryonic development in several genetic models through mechanisms not understood. Very few functional substrate/adaptor pairs for Cul3 ubiquitin ligases have been identified. Here, we show that Cul3 knockdown in human cells results in abnormal actin stress fibers and distorted cell morphology, owing to impaired ubiquitination and degradation of small GTPase RhoA. We identify a family of RhoA-binding BTB domain adaptors conserved from insects to mammals, designated BACURDs. BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Dysfunction of the Cul3/BACURD complex decreases cell migration potential and impairs RhoA-mediated convergent extension movements during Xenopus gastrulation. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.
Chen
Yuezhou
Y
College of Life Science, Peking University, Beijing 100871, China.
Yang
Zhenxiao
Z
Meng
Min
M
Zhao
Yue
Y
Dong
Na
N
Yan
Hongming
H
Liu
Liping
L
Ding
Mingxiao
M
Peng
H Benjamin
HB
Shao
Feng
F
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement; D048430:Cell Shape; D017124:Conserved Sequence; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D019143:Evolution, Molecular; D054262:Gastrulation; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; C503645:CUL3 protein, human; C503647:Cul3 protein, Drosophila; D044842:Cullin Proteins; D029721:Drosophila Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D029867:Xenopus Proteins; D020742:rhoA GTP-Binding Protein