Abstract
Ubiquitination is a versatile post-translational modification that regulates a multitude of cellular processes. Its versatility is based on the ability of ubiquitin to form multiple types of polyubiquitin chains, which are recognized by specific ubiquitin receptors to induce the required cellular response. Linear ubiquitin chains are linked through Met 1 and have been established as important players of inflammatory signalling and apoptotic cell death. These chains are generated by a ubiquitin E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) that is thus far the only E3 ligase capable of forming linear ubiquitin chains. The complex consists of three subunits, HOIP, HOIL-1L and SHARPIN, each of which have specific roles in the observed biological functions of LUBAC. Furthermore, LUBAC has been found to be associated with OTULIN and CYLD, deubiquitinases that disassemble linear chains and counterbalance the E3 ligase activity of LUBAC. Gene mutations in HOIP, HOIL-1L and OTULIN are found in human patients who suffer from autoimmune diseases, and HOIL-1L mutations are also found in myopathy patients. In this paper, we discuss the mechanisms of linear ubiquitin chain generation and disassembly by their respective enzymes and review our current understanding of their biological functions and association with human diseases.
Highlights
Post-translational modifications of proteins extend their functional landscape and allow rapid changes in their behaviour in response to stimuli without the need for protein synthesis de novo
When linear ubiquitin chain assembly complex (LUBAC) was discovered in 2006, it was initially thought to be composed of only two subunits termed HOIL1-interacting protein (HOIP)/RNF31 and haem-oxidized IRP2 ubiquitin ligase1L (HOIL-1L)/RBCK1, which associate into a highmolecular-weight complex of unknown stoichiometry [2]
Since the first biochemical study of LUBAC-induced linear ubiquitination was reported by Iwai and co-workers in 2006 [2], our understanding of LUBAC and linear ubiquitination has expanded significantly from molecular and cellular functions to its impact on in vivo roles and human diseases
Summary
Post-translational modifications of proteins extend their functional landscape and allow rapid changes in their behaviour in response to stimuli without the need for protein synthesis de novo. In 2006, a multi-subunit complex termed linear ubiquitin chain assembly complex (LUBAC) was identified to be responsible for their synthesis [2] and it was later shown that they are required for the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) transcription factor and play important roles in immune and inflammatory signalling processes [3,4] Since their functional roles have been extended to include regulation of cell death, T- and B-cell development, mouse embryonic development, heat tolerance in flies, and cancer and autoimmune diseases in humans [5,6,7,8,9,10]. License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited
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