Less is known about the poly-Ub linkage specificity of deubiquitinating enzymes (DUBs), but the current view remains that Ubiquitin C-terminal hydrolases (UCHs) mainly cleave ubiquitin precursors, whereas ubiquitin specific proteases (USPs), ovarian tumor containing proteases (OTUs), the Josephin and the JAB1/MPN/MOV34 (JAMM) proteases all have a various degree of promiscuity towards different poly-Ub linkages or cleave mono-ubiquitin from protein substrates [2• and 4]. Noncovalent interactions also contribute to the complexity of ubiquitin signaling. At least 20 different types of domains have

Selleckchem NVP-BKM120 been identified in ubiquitin binding proteins (UBP) that interact with ubiquitin in a noncovalent manner to regulate the fate of ubiquitinated proteins [5 and 6]. buy INCB024360 It is therefore not surprising

that many genes linked to ubiquitin processing and recognition have been found to be mutated within the context of human diseases (Figure 1). Interestingly, neurological disorders appear to be particularly vulnerable to mutations in ubiquitin conjugating and deconjugating enzymes. For instance, mutations in the parkin gene encoding for a E3 ubiquitin ligase and the uchl1 gene encoding for a ubiquitin C-terminal hydrolase (UCH-L1) are associated with early-onset autosomal recessive forms of Parkinson’s disease [ 7]. Also, mutations in the E6-AP gene coding for the ubiquitin ligase E6-AP (UBE3A) are linked to the Angelman Syndrome Mirabegron [ 8], and single point mutations in the ubiquitin ligase HUWE/Mule/ARF-BP are the cause of mental retardation syndromic X-linked Turner type (MRXST), possibly through aberrant DNA repair [ 9 and 10]. In addition, the familial amyotrophic lateral sclerosis and Machado-Joseph disease/spinocerebellar ataxia

type 3 is directly linked to mutation in a gene encoding for a deubiquitinating enzyme (Ataxin-3), which is involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP [ 11]. Aberrant expression/mutations of many E3 ubiquitin ligases and DUBs are also found in diverse cancer types (reviewed in [12, 13 and 14]). In some cases, E3 ligases and DUBs act as tumor suppressors, such as the von Hippel Lindau vhl gene encoding for an E3 ubiquitin ligase, where mutations are the underlying cause of susceptibility to pheochromocytoma (PCC) [ 15]. Another example is the cyld gene encoding for the deubiquitinase CYLD, and direct mutation in the protease domain have been linked to the turban tumor syndrome (cylindromatosis) [ 16]. These cases as well as many others of this type suggest that in some way the homeostasis and dynamics of ubiquitinated proteins is altered either as a consequence or potentially as an underlying cause contributing to disease pathogenesis.