Abstract
The linear ubiquitin chain assembly complex (LUBAC) is a ubiquitin ligase composed of the Heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L-interacting protein (HOIP), and Shank-associated RH domain interactor (SHARPIN) subunits. LUBAC specifically generates the N-terminal Met1-linked linear ubiquitin chain and regulates acquired and innate immune responses, such as the canonical nuclear factor-κB (NF-κB) and interferon antiviral pathways. Deubiquitinating enzymes, OTULIN and CYLD, physiologically bind to HOIP and control its function by hydrolyzing the linear ubiquitin chain. Moreover, proteins containing linear ubiquitin-specific binding domains, such as NF-κB-essential modulator (NEMO), optineurin, A20-binding inhibitors of NF-κB (ABINs), and A20, modulate the functions of LUBAC, and the dysregulation of the LUBAC-mediated linear ubiquitination pathway induces cancer and inflammatory, autoimmune, and neurodegenerative diseases. Therefore, inhibitors of LUBAC would be valuable to facilitate investigations of the molecular and cellular bases for LUBAC-mediated linear ubiquitination and signal transduction, and for potential therapeutic purposes. We identified and characterized α,β-unsaturated carbonyl-containing chemicals, named HOIPINs (HOIP inhibitors), as LUBAC inhibitors. We summarize recent advances in elucidations of the pathophysiological functions of LUBAC-mediated linear ubiquitination and identifications of its regulators, toward the development of LUBAC inhibitors.
Highlights
Ubiquitin, a 76-residue (8.6 kDa) small globular protein, is evolutionally conserved in most eukaryotes
We further identified that mind bomb homolog 2 (MIB2) is an E3 that leads to the proteasomal degradation of CYLD, and MIB2 affects linear ubiquitin chain assembly complex (LUBAC)-mediated nuclear factor-κB (NF-κB) activation [108]
We hypothesized that the aggregable proteins in wisp inclusions may be initially conjugated with K48-linked ubiquitin chains; they seem to be resistant to the proteasomal degradation due to misfolding (Figure 6)
Summary
A 76-residue (8.6 kDa) small globular protein, is evolutionally conserved in most eukaryotes. The K48-linked polyubiquitin chain, which is the most common, serves as a typical proteasomal degradation signal, and the K63-linked polyubiquitin chain, the second most predominant linkage, is involved in non-proteasomal functions, such as signal transduction and DNA repair [1,6] In addition to these Lys-linked polyubiquitin chains, the N-terminal Met1(M1)-linked linear polyubiquitination is generated by the E3 complex, named the linear ubiquitin chain assembly complex (LUBAC). Specific residues of ubiquitin are chemically modified, by phosphorylation, acetylation, and ADP-ribosylation, and these modifications regulate the pathophysiological functions of ubiquitination These diverse ubiquitin linkages exhibit multiple functions in a system called the “ubiquitin code” [6], in which E1, E2, and E3 function as “writers”, DUBs are “erasers”, and ubiquitin-binding proteins serve as “decoders”. We focus on the structures, catalytic mechanisms, inhibitors, and pathophysiological functions of the LUBAC-mediated “linear ubiquitin code”, revealed by studies using human cell lines, diseases, and phenotypes of genetically deficient mice
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