The Role of E3s in Regulating Pluripotency of Embryonic Stem Cells and Induced Pluripotent Stem Cells

Abstract

Pluripotent embryonic stem cells (ESCs) are derived from early embryos and can differentiate into any type of cells in living organisms. Induced pluripotent stem cells (iPSCs) resemble ESCs, both of which serve as excellent sources to study early embryonic development and realize cell replacement therapies for age-related degenerative diseases and other cell dysfunction-related illnesses. To achieve these valuable applications, comprehensively understanding of the mechanisms underlying pluripotency maintenance and acquisition is critical. Ubiquitination modifies proteins with Ubiquitin (Ub) at the post-translational level to monitor protein stability and activity. It is extensively involved in pluripotency-specific regulatory networks in ESCs and iPSCs. Ubiquitination is achieved by sequential actions of the Ub-activating enzyme E1, Ub-conjugating enzyme E2, and Ub ligase E3. Compared with E1s and E2s, E3s are most abundant, responsible for substrate selectivity and functional diversity. In this review, we focus on E3 ligases to discuss recent progresses in understanding how they regulate pluripotency and somatic cell reprogramming through ubiquitinating core ESC regulators.

Keywords: embryonic stem cells; induced pluripotent stem cells; pluripotency; ubiquitination.

Figure 1

E3s are involved in regulating pluripotency. Pluripotent cells can be derived from teratomas or early embryos. Pluripotency can also be restored through introducing defined factors in somatic cells to generate iPSCs. Multiple E3s have been identified for their critical roles in monitoring the stability or activity of pluripotency regulators.

Figure 2

The process of ubiquitination. E1 activates Ub to form the E1-Ub intermediate. Next, E2 catalyzes transthiolation reaction to transfer Ub from the E1-Ub complex to its active C site. An E3 ligase is responsible for the final reaction. RING-type E3s facilitate direct Ub transfer from E2s to substrates, whereas HECT-type and RBR-type E3s adopt two-step reactions for Ub conjugation. Substrate proteins can be modified by mono-ub or poly-ub chains. A poly-Ub chain can be homotypic with only one linkage type or heterotypic with mixed or branched linkages.