OTUB1-mediated inhibition of ubiquitination: a growing list of effectors, multiplex mechanisms, and versatile functions

Abstract

Protein ubiquitination plays a pivotal role in protein homeostasis. Ubiquitination may regulate the stability, activity, protein-protein interaction, and localization of a protein. Ubiquitination is subject to regulation by two groups of counteracting enzymes, the E3 ubiquitin ligases and deubiquitinases. Consistently, deubiquitinases are involved in essentially all biological processes. OTUB1, an OTU-family deubiquitinase, is a critical regulator of development, cancer, DNA damage response, and immune response. OTUB1 antagonizes the ubiquitination of a wide-spectrum of proteins through at least two different mechanisms. Besides direct deubiquitination, OTUB1 can also inhibit ubiquitination by non-canonically blocking ubiquitin transfer from certain ubiquitin-conjugases (E2). In this review, we start with a general background of protein ubiquitination and deubiquitination. Next, we introduce the basic characteristics of OTUB1 and then elaborate on the updated biological functions of OTUB1. Afterwards, we discuss potential mechanisms underlying the versatility and specificity of OTUB1 functions. In the end, we discuss the perspective that OTUB1 can be a potential therapeutic target for cancer.

Keywords: OTUB1; cancer; degradation; deubiquitinase; ubiquitin-conjugating enzyme; ubiquitination.

FIGURE 1

Ubiquitination and deubiquitination.

FIGURE 2

Comparison between domain arrangement of OTUB1 and OTUB2.

FIGURE 3

Two mechanisms by which OTUB1 antagonizes ubiquitination. (A) OTUB1 interacts with a ubiquitinated protein and removes ubiquitin from it. (B) OTUB1 interacts with E2∼Ub conjugate and locks it in an inactive conformation, preventing ubiquitin transfer to an “effector”. denotes ubiquitin.

FIGURE 4

Function and regulation of OTUB1 in cancer.

FIGURE 5

OTUB1 regulates DNA damage response (A).OTUB1 can either promote or delay DNA damage repair through targeting DNA damage foci and MSH2. denotes a promoting effect while denotes an inhibiting effect. (B) By inhibiting ubiquitination of P53 and MDMX, OTUB1 can promote cellular apoptosis upon DNA damage. denotes a promoting effect while denotes an inhibiting effect.

FIGURE 6

OTUB1 in immunity.

FIGURE 7

Regions of OTUB1 interacting with other proteins. Regions of OTUB1 are depicted on the left as horizontal bars while the names of proteins interacting with these regions are shown on the right.