CRL2LRR-1 Targets a CDK Inhibitor for Cell Cycle Control in C. elegans and Actin-Based Motility Regulation in Human Cells

SummaryThe Cip/Kip CDK inhibitor (CKI) p21Cip1/WAF1 has a critical role in the nucleus to limit cell proliferation by inhibiting CDK-cyclin complexes. In contrast, cytoplasmic p21 regulates cell survival and the actin cytoskeleton. These divergent functions for p21 in different cellular compartments suggest the necessity for complex regulation. In this study, we identify the CRL2LRR-1 ubiquitin ligase as a conserved regulator of Cip/Kip CKIs that promotes the degradation of C. elegans CKI-1 and human p21. The nematode CRL2LRR-1 complex negatively regulates nuclear CKI-1 levels to ensure G1-phase cell cycle progression in germ cells. In contrast, human CRL2LRR1 targets cytoplasmic p21, acting as a critical regulator of cell motility that promotes a nonmotile stationary cell state by preventing p21 from inhibiting the Rho/ROCK/LIMK pathway. Inactivation of human CRL2LRR1 leads to the activation of the actin-depolymerizing protein cofilin, dramatic reorganization of the actin cytoskeleton, and increased cell motility.

▸ C. elegans CRL2LRR-1 promotes cell cycle progression via degradation of nuclear CKI-1 ▸ Human CRL2LRR1 targets the degradation of the cytoplasmic pool of p21Cip1 ▸ CRL2LRR1 regulates the actin-depolymerizing protein cofilin via p21Cip1 degradation ▸ Loss of CRL2LRR1 induces actin cytoskeletal reorganization and increased cell motility