Abstract
The small modifier protein, ubiquitin, holds a special place in eukaryotic biology because of its myriad post-translational effects that control normal cellular processes and are implicated in various diseases. By being covalently conjugated onto other proteins, ubiquitin changes their interaction landscape - fostering new interactions as well as inhibiting others - and ultimately deciding the fate of its substrates and controlling pathways that span most cell physiology. Ubiquitin can be attached onto other proteins as a monomer or as a poly-ubiquitin chain of diverse structural topologies. Among the types of poly-ubiquitin species generated are ones detached from another substrate - comprising solely ubiquitin as their constituent - referred to as unanchored, or free chains. Considered to be toxic byproducts, these species have recently emerged to have specific physiological functions in immune pathways and during cell stress. Free chains also do not appear to be detrimental to multi-cellular organisms; they can be active members of the ubiquitination process, rather than corollary species awaiting disassembly into mono-ubiquitin. Here, we summarize past and recent studies on unanchored ubiquitin chains, paying special attention to their emerging roles as second messengers in several signaling pathways. These investigations paint complex and flexible outcomes for free ubiquitin chains, and present a revised model of unanchored poly-ubiquitin biology that is in need of additional investigation.
Highlights
Specialty section: This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Cell and Developmental
Much of our knowledge of unanchored poly-Ub arose from research on the best-known deubiquitinating enzyme (DUB) that processes it, Ubspecific protease 5 (USP5)
USP5 siRNA or Ub GG expression caused increased ubiquitination of p53. Since this increased ubiquitination, which could be a degradation signal, counter-intuitively coincides with slowed p53 turnover, the authors argued that the effects of USP5 suppression on p53 activity are mediated by the accumulation of unanchored Ub chains that outcompete ubiquitinated p53 at the proteasome and extend its half-life (Dayal et al, 2009); the study did not directly examine whether p53 ubiquitination is consistent with a degradation signal, or whether its binding to the proteasome is impaired in the presence of mutant Ub
Summary
Lys Scaffolding to facilitate protein interactions Acts as an interaction point for the formation and activation of various complexes and pathways: Activation of NF-κB transcription factor (Deng et al, 2000; Wang et al, 2001; Xia et al, 2009; Xu et al, 2009a) DNA repair (Spence et al, 1995; Hoege et al, 2002; Sobhian et al, 2007; Doil et al, 2009; Huang et al, 2009; Stewart et al, 2009; Al-Hakim et al, 2010) Innate immune responses (Gack et al, 2007) Mitophagy (Cunningham et al, 2015; Ordureau et al, 2015) Protein sorting (Lauwers et al, 2009; Huang et al, 2013) Assembly of protein complexes that drive mRNA splicing and translation (Spence et al, 2000; Bellare et al, 2008; Song et al, 2010; Silva et al, 2015) Propagation of Wnt signaling (Tauriello and Maurice, 2010) Lysosomal degradation.
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