Dataset Information

The crosstalk between CRL5 and APC/C E3 ligases regulates metastasis and chemo-sensitivity of cancer cells

ABSTRACT: Cullin-RING ligases (CRLs) and the anaphase-promoting complex/cyclosome (APC/C) are two major multi-subunit ubiquitin ligases essential for protein homeostasis. The underlying mechanism and biological consequence of their crosstalk remain elusive. Here, we employed tandem affinity purification followed by LC-MS/MS and identified APC11—the RING subunit of APC/C—as a bona fide binding partner of CUL5, the scaffold of CRL5. On one hand, APC11 interacts with CUL5 and inhibits its neddylation. Consequently, APC11 knockdown enhances CUL5 neddylation by promoting its interaction with the neddylation E2 UBE2F. This leads to the degradation of SOCS3, a substrate receptor of CRL5, and the subsequent accumulation of its substrate, integrin Integrin β1, ultimately promoting cancer metastasis. On the other hand, CUL5-APC11 binding stabilizes APC11 by facilitating its atypical K27/K29/K33-linked polyubiquitylation at Lys83, a process catalyzed by ITCH E3 ligase. CUL5 loss delays mitotic exit, induces aneuploidy, and sensitizes cancer cells to the microtubule-targeting drug paclitaxel by destabilizing APC11. Collectively, our study revealed a new cross-talk between CUL5 and APC11 of two major E3 ligases, and targeting this cross-talk could provide a new strategy for blocking metastasis and triggering chemo-sensitization.

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ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Danrui Cui

LAB HEAD: Yongchao Zhao

PROVIDER: PXD068961 | Pride | 2026-01-23

REPOSITORIES: Pride

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The Crosstalk Between CRL5 and APC/C E3 Ligases Regulates Metastasis and Chemosensitivity of Cancer Cells.

Cui Danrui D Qu Ruirui R Li Tianqi T Wang Linchen L Chen Xiaoyu X Shao Shengpeng S Liang Xue X Xu Jun J Sun Yi Y Xiong Xiufang X Zhao Yongchao Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20251029 3

Cullin-RING ligases (CRLs) and the anaphase-promoting complex/cyclosome (APC/C) are two major multi-subunit ubiquitin ligases essential for protein homeostasis. The underlying mechanism and biological consequence of their crosstalk remain elusive. Here, tandem affinity purification followed by LC-MS/MS is employed, and identified APC11-the RING subunit of APC/C-as a bona fide binding partner of CUL5, the scaffold of CRL5. On one hand, APC11 interacts with CUL5 and inhibits its neddylation. Conse ...[more]

PMID: 41159544

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Project description:Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. While the role of ubiquitin (Ub) ligase PARKIN in mitophagy has been extensively studied, increasing evidence suggests the existence of PARKIN-independent mitophagy in highly metabolically active organs such as the heart. Here, we identify a crucial role for Cullin-RING Ub ligase 5 (CRL5) in basal mitochondrial turnover in cardiomyocytes. CRL5 is a multi-subunit Ub ligase comprised by the catalytic RING box protein RBX2 (also known as SAG), scaffold protein Cullin 5 (CUL5), and a substrate-recognizing receptor. Analysis of the mitochondrial outer membrane-interacting proteome uncovered a robust association of CRLs with mitochondria. Subcellular fractionation, immunostaining, and immunogold electron microscopy established that RBX2 and Cul5, two core components of CRL5, localizes to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, and increased cell death in cardiomyocytes. In vivo, deletion of the Rbx2 gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. Notably, the action of RBX2 in mitochondria is not dependent on PARKIN, and PARKIN gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 in mitochondria. Proteomics and biochemical analyses further revealed a global impact of RBX2 deficiency on the mitochondrial proteome and identified several mitochondrial proteins as its putative substrates. These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that controls mitophagy under physiological conditions in a PARKIN-independent, PINK1-dependent manner, thereby regulating cardiac homeostasis.

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