Cezanne/ OTUD 7B is a cell cycle‐regulated deubiquitinase that antagonizes the degradation of APC /C substrates

Abstract

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. Since APC/C promotes the degradation of mitotic cyclins, it controls cell cycle-dependent oscillations in cyclin-dependent kinase (CDK) activity. Both CDKs and APC/C control a large number of substrates and are regulated by analogous mechanisms, including cofactor-dependent activation. However, whereas substrate dephosphorylation is known to counteract CDK, it remains largely unknown whether deubiquitinating enzymes (DUBs) antagonize APC/C substrate ubiquitination during mitosis. Here, we demonstrate that Cezanne/OTUD7B is a cell cycle-regulated DUB that opposes the ubiquitination of APC/C targets. Cezanne is remarkably specific for K11-linked ubiquitin chains, which are formed by APC/C in mitosis. Accordingly, Cezanne binds established APC/C substrates and reverses their APC/C-mediated ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes errors in mitotic progression and formation of micronuclei. These data highlight the importance of tempered APC/C substrate destruction in maintaining chromosome stability. Furthermore, Cezanne is recurrently amplified and overexpressed in numerous malignancies, suggesting a potential role in genome maintenance and cancer cell proliferation.

Impressionist portraits of mitotic exit: APC/C, K11-linked ubiquitin chains and Cezanne

“…In summary, our recent study describes a novel, DUB-dependent mechanism which restrains APC/ C activity during mitosis, thereby contributing to substrate degradation kinetics and proper mitotic progression [31] (Figure 1). We envision that Cezanne could be involved in a phenomenon referred to as substrates ordering, meaning that different APC/C substrates are degraded at different rates as cells exit mitosis and progress through G1-phase.…”

“…In order to address this discrepancy, we examined Cezanne function and abundance in actively dividing cells [31]. Since K11-linked ubiquitin chains are (i) important regulators of cell division and (ii) the product of cell cycle-regulated enzymes like UBE2S and the APC/C, we hypothesized that Cezanne could also be a cell cycle-regulated protein.…”

“…It is important to note that in these assays, the interaction observed between Cezanne and these substrates is ubiquitin independent. Since Cezanne is able to bind directly to substrates [31], and also can directly interact with K11-linked ubiquitin chains, this raises the interesting possibility that Cezanne engages substrates through simultaneous, multi-valent interactions with both targets and ubiquitin chains. Furthermore, these interactions appeared to be cell cycle regulated, indicating that currently unknown post-translational mechanisms determine the ability of Cezanne to recognize substrates.…”

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…112,113 CYLD is more likely to act on linear ubiquitination and the K63 linkage Ub chain. 114 Similarly, OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) specifically acts on K48-linked ubiquitination, 115,116 with Cezanne specifically removing the K11 linkage Ub chain, 117,118 and TRABID specifically recognizing the K29-linked or K33-linked Ub chain. 119 These specific Ub-type deubiquitinating enzymes cannot remove the last molecule of Ub-modified on the substrate, which may generate a monoubiquitinated substrate protein.…”

Emerging Roles and Research Tools of Atypical Ubiquitination

“…Moreover, Thomas Bonacci et al. demonstrated that Cezanne has tremendous selectivity for K11‐linked chains and can directly deubiquitinate K11‐linked modified substrates, including Cyclin B and Securin, thus acting as a cell cycle‐regulated deubiquitinase that counteracts the ubiquitination of APC/C targets . In addition, studies have found that the deubiquitinases USP8 and USP19 stabilize Caspase‐1 and Beclin‐1, respectively, by removing the K11‐linked chains from these proteins, thus influencing type I interferon (IFN) signaling as well as cellular antiviral immunity …”