Deubiquitylation of deubiquitylases

Abstract

Deubiquitylating enzymes (DUBs) reverse the ubiquitylation of target proteins, thereby regulating diverse cellular functions. In contrast to the plethora of research being conducted on the ability of DUBs to counter the degradation of cellular proteins or auto-ubiquitylated E3 ligases, very little is known about the mechanisms of DUB regulation. In this review paper, we summarize a novel possible mechanism of DUB deubiquitylation by other DUBs. The available data suggest the need for further experiments to validate and characterize this notion of 'Dubbing DUBs'. The current studies indicate that the idea of deubiquitylation of DUBs by other DUBs is still in its infancy. Nevertheless, future research holds the promise of validation of this concept.

Keywords: auto-regulation; deubiquitylating DUBs; proteasome degradation; self-deubiquitylation; ubiquitylation.

Figure 1.

The ubiquitin proteasome system. Ubiquitylation occurs through the subsequent actions of E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme) and E3 enzymes (ubiquitin ligase) on the mediation of ubiquitin ligation to target proteins. DUBs counteract E3 ligase-mediated ubiquitylation and recycle the ubiquitin molecules for further use.

Figure 2.

Catalytic roles of DUBs. DUBs contribute to four major cellular events: (a) editing of ubiquitin chains, (b) recycling of ubiquitin, (c) processing of ubiquitin precursors and (d) reversal of ubiquitin conjugation.

Figure 3.

Monoubiquitylation of deubiquitylating enzymes by (a) Carp2, (b) Praja1, (c) Murf1 ubiquitin ligase and (d) their mixture (Carp2, Praja1 and Murf1). The circles on the left and right represent high and low ubiquitylating DUBs, respectively. The overlapping area between the two circles represents DUBs that undergo intermediate ubiquitylation. (a) Level of ubiquitylation of deubiquitylating enzymes by Carp2 ubiquitin ligase. (b) Level of ubiquitylation of deubiquitylating enzymes by Praja1 ubiquitin ligase. (c) Level of ubiquitylation of deubiquitylating enzymes by Murf1 ubiquitin ligase. (d) Level of ubiquitylation of deubiquitylating enzymes by Carp2, Praja1 and Murf1 ubiquitin ligases. Inferred from Loch & Strickler [34].

Figure 4.

Representations of the microarray data inferred from Loch & Strickler [34]. (a) Removal of monoubiquitin from JOSD1 by PLP2 deubiquitylating enzyme. (b) The figure illustrates JOSD1 to be a putative substrate of USP21c deubiquitylating enzyme as per its capability to completely remove the ubiquitin chains.

Figure 5.

The potential interactors of (a) USP2, (b) USP8, (c) USP15, (d) USP21, (e) USP28 and (f) PLP2 as illustrated in STRING: Functional Protein Association Network software [40].

Figure 6.

Dubbing DUBs. The figure represents DUB as a substrate as well as an enzyme and hypothetically presents the possible mechanisms of (a) ubiquitin chain shortening (i.e. incomplete removal of ubiquitin molecules), (b) ubiquitin conjugation reversal (i.e. complete removal of ubiquitin molecules), (c) complete deubiquitylation of ubiquitylated DUB substrate by some other DUB and (d) complete deubiquitylation of itself (i.e. self-deubiquitylation).