The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases

Abstract

Machado-Joseph disease (MJD) is a devastating and incurable neurodegenerative disease characterised by progressive ataxia, difficulty speaking and swallowing. Consequently, affected individuals ultimately become wheelchair dependent, require constant care, and face a shortened life expectancy. The monogenic cause of MJD is expansion of a trinucleotide (CAG) repeat region within the ATXN3 gene, which results in polyglutamine (polyQ) expansion within the resultant ataxin-3 protein. While it is well established that the ataxin-3 protein functions as a deubiquitinating (DUB) enzyme and is therefore critically involved in proteostasis, several unanswered questions remain regarding the impact of polyQ expansion in ataxin-3 on its DUB function. Here we review the current literature surrounding ataxin-3's DUB function, its DUB targets, and what is known regarding the impact of polyQ expansion on ataxin-3's DUB function. We also consider the potential neuroprotective effects of ataxin-3's DUB function, and the intersection of ataxin-3's role as a DUB enzyme and regulator of gene transcription. Ataxin-3 is the principal pathogenic protein in MJD and also appears to be involved in cancer. As aberrant deubiquitination has been linked to both neurodegeneration and cancer, a comprehensive understanding of ataxin-3's DUB function is important for elucidating potential therapeutic targets in these complex conditions. In this review, we aim to consolidate knowledge of ataxin-3 as a DUB and unveil areas for future research to aid therapeutic targeting of ataxin-3's DUB function for the treatment of MJD and other diseases.

Keywords: deubiquitinase; neurodegeneration; polyglutamine repeat; spinocerebellar ataxia type-3; ubiquitin proteasome system.

Figure 1.. As a deubiquitinating enzyme in the ubiquitin-proteasome system, ataxin-3 functions in many ways.

(A) Preferentially cleaves K48- and K63-linked lysine ubiquitination. (B) Preferentially cleaves K63-linked ubiquitin chains within mixed linkage chains. (C) Is more efficient at cleaving ubiquitination on threonine than lysine residues. (D) Preferentially cleaves polyubiquitin chains comprised of at least four ubiquitin moieties and is inefficient at cleaving polyubiquitin chains of less than six ubiquitin moieties. (E) Functions as a chain-editing DUB that cleaves the first 1–3 ubiquitin moieties from a polyubiquitin chain and is inefficient at cleaving subsequent ubiquitin moieties. (F) Is proposed to trim non-K48-linked ubiquitin linkages to facilitate optimal delivery of substrates to the proteasome. K is lysine, T is threonine, DUB is deubiquitinating enzyme. Figure created with BioRender.com.

Figure 2.. Schematic representation of ataxin-3's structure.

The N-terminus of ataxin-3 contains the deubiquitinating Josephin domain within which two ubiquitin-binding sites and the polyubiquitin chain cleaving catalytic triad are located. The C-terminus of ataxin-3 represents the ubiquitin binding domain, which contains the three ubiquitin-interacting motifs (UIMs), a nuclear localisation signal (NLS), and a polyQ repeat which is expanded in MJD. Important lysine ubiquitination sites on ataxin-3 are indicated in blue. Figure created with BioRender.com.

Figure 3.. Summary of proposed neuroprotective functions of wild-type ataxin-3 protein.

(A) Wild-type ataxin-3 appears to suppress degeneration induced by pathogenic polyQ proteins in Drosophila [121,162,165] and some mouse models [159], but not in other rodent models [166–168]. (B) The protective effects of wild-type ataxin-3 require its DUB functions. (C) Wild-type ataxin-3 cleaves polyubiquitin chains on misfolded/aggregated proteins, allowing them to be recognised by HDAC6 and therefore sequestered to aggresomes [96,169]. (D) Wild-type ataxin-3 has been implicated in modulating C-terminal TDP-43 fragments, a molecular hallmark of ALS [170]. ATXN3-exp denotes polyQ-expanded ataxin-3, HTT-exp denotes polyQ-expanded huntingtin, CTF is C-terminal TDP-43 fragment. Figure created with BioRender.com.

Figure 4.. Ataxin-3 can repress transcription via at least two mechanisms.

(A) The C-terminal region of the ataxin-3 protein (C-ataxin-3) binds to CREB-binding protein (CBP) and p300 co-activators and represses their transcriptional activity, preventing acetylation of histones, and resulting in chromatin being more tightly packed and made inaccessible to transcription factors and RNA pol II. As a result, transcription of the target gene is repressed. (B) The N-terminal region of ataxin-3 protein (N-ataxin-3) binds to histones and prevents their acetylation by HATs, which also results in repression of transcription by a similar mechanism as (A). TF is transcription factor, Ac is acetyl group, RNA pol II is RNA polymerase II, HAT is histone acetyltransferase. Figure created with BioRender.com.