Wolfgang Dubiel | Trends in Biochemical Sciences: Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mammalian Cell Differentiation

Highlights

Whereas CRL1 complexes often target cell cycle regulators for degradation, such as cyclins and the cell cycle inhibitors p21 and p27, most members of the CRL4 family are essential for chromatin stability and DNA repair. These findings support the emerging concept that different CRL families evolved to fulfill specialized cellular functions.

In contrast to CUL1 and CUL4, which are predominantly in the nucleus, CUL3 is mostly localized to, and functional in, the cytoplasm.

There are approximately 180 BTB proteins encoded in the human genome. However, so far only approximately 50 BTB proteins have been confirmed as substrate receptors (SR) in CRL3 complexes.

Inhibition of RHOA signaling by targeting RHOA for degradation via CRL3-dependent ubiquitylation transfers MSCs to a more sessile phenotype and accelerates cell differentiation.

There is increasing interest in MSCs in regenerative medicine with the potential to find novel cures for a variety of diseases. Understanding the exact roles of CRL3s in MSC differentiation may catalyze leaps in MSC research and regenerative medicine.

Specificity of the ubiquitin proteasome system is controlled by ubiquitin E3 ligases, including their major representatives, the multisubunit cullin-RING ubiquitin (Ub) ligases (CRLs). More than 200 different CRLs are divided into seven families according to their cullin scaffolding proteins (CUL1–7) around which they are assembled. Research over two decades has revealed that different CRL families are specialized to fulfill specific cellular functions. Whereas many CUL1-based CRLs (CRL1s) ubiquitylate cell cycle regulators, CRL4 complexes often associate with chromatin to control DNA metabolism. Based on studies about differentiation programs of mesenchymal stem cells (MSCs), including myogenesis, neurogenesis, chondrogenesis, osteogenesis and adipogenesis, we propose here that CRL3 complexes evolved to fulfill a pivotal role in mammalian cell differentiation.

Link: https://www.sciencedirect.com/science/article/pii/S0968000417302232