BMB Reports 2019; 52(2): 119-126
E3 ubiquitin ligases and deubiquitinases as modulators of TRAIL-mediated extrinsic apoptotic signaling pathway
Seon Min Woo and Taeg Kyu Kwon*
Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea
Correspondence to: Tel: +82-53-580-3882; Fax: +82-53-580-3795; E-mail:
Received: November 19, 2018; Published online: February 28, 2019.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

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The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) initiates the extrinsic apoptotic pathway through formation of the death-inducing signaling complex (DISC), followed by activation of effector caspases. TRAIL receptors are composed of death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and osteoprotegerin. Among them, only DRs activate apoptotic signaling by TRAIL. Since the levels of DR expressions are higher in cancer cells than in normal cells, TRAIL selectively activates apoptotic signaling pathway in cancer cells. However, multiple mechanisms, including down-regulation of DR expression and pro-apoptotic proteins, and up-regulation of anti-apoptotic proteins, make cancer cells TRAIL-resistant. Therefore, many researchers have investigated strategies to overcome TRAIL resistance. In this review, we focus on protein regulation in relation to extrinsic apoptotic signaling pathways via ubiquitination. The ubiquitin proteasome system (UPS) is an important process in control of protein degradation and stabilization, and regulates proliferation and apoptosis in cancer cells. The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and deubiquitinases (DUBs), which determine protein stability. Regulation of the UPS may be an attractive target for enhancement of TRAIL-induced apoptosis. Our review provides insight to increasing sensitivity to TRAIL-mediated apoptosis through control of post-translational protein expression.
Keywords: Deubiquitinase, DISC, E3 ligase, Extrinsic pathway, TRAIL
Fig. 1. The process of the ubiquitin proteasome system (UPS). 1) Ubiquitin (Ub) is activated by E1 activating enzymes in an ATP-dependent manner, then transferred to E2 conjugating enzymes. E2 conjugating enzymes can recruit E3 ligases enzymes with target substrates. E3 ligase enzymes directly catalyze transfer of activated ubiquitin from E2 conjugating enzymes to substrates, leading to the formation of polyubiquitin chains on target substrates. This process is called ubiquitination. Lys48- and Lys11-linked polyubiquitin chains usually induce degradation of target substrate through proteasome activation. Conversely, Lys63-linked polyubiquitin chains regulate cellular signaling and trafficking. 2) Ubiquitination of target substrate is reversed by deubiquitinases (DUBs). DUBs are critical roles for regulating the function of ubiquitinated proteins by removal of polyubiquitin chains. This process is called deubiquitination. In addition, ubiquitin released from substrates by DUBs can be recycled for activation of ubiquitination.

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