The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC

Fuseya, Yasuhiro; Fujita, Hiroaki; Kim, Minsoo; Ohtake, Fumiaki; Nishide, Akira; Sasaki, Katsuhiro; Saeki, Yasushi; Tanaka, Keiji; Takahashi, Ryōsuke; Iwaï, Kazuhiro

doi:10.1038/s41556-020-0517-9

Cited by 78 publications

(141 citation statements)

References 63 publications

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“…Non-lysine ubiquitination has been observed previously [45][46][47][48], however this is the first report of an RBR E3 ligase generating these unique linkage types. These findings were partly confirmed by Fuseya et al [49] who more recently describe that HOIL-1L attaches O-linked ubiquitin to HOIP and SHARPIN, but, interestingly, ubiquitinates itself on lysine residues. While these discrepancies need further investigation, HOIL-1L and O-linked ubiquitin appear to be important regulators of LUBAC activity.…”

Section: Determinants Of Ubiquitin Chain-type Specificitysupporting

confidence: 60%

Chain reactions: molecular mechanisms of RBR ubiquitin ligases

Cotton

Lechtenberg

2020

Biochemical Society Transactions

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Ubiquitination is a fundamental post-translational modification that regulates almost all aspects of cellular signalling and is ultimately catalysed by the action of E3 ubiquitin ligases. The RING-between-RING (RBR) family of E3 ligases encompasses 14 distinct human enzymes that are defined by a unique domain organisation and catalytic mechanism. Detailed characterisation of several RBR ligase family members in the last decade has revealed common structural and mechanistic features. At the same time these studies have highlighted critical differences with respect to autoinhibition, activation and catalysis. Importantly, the majority of RBR E3 ligases remain poorly studied, and thus the extent of diversity within the family remains unknown. In this mini-review we outline the current understanding of the RBR E3 mechanism, structure and regulation with a particular focus on recent findings and developments that will shape the field in coming years.

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Section: Determinants Of Ubiquitin Chain-type Specificitysupporting

confidence: 60%

Chain reactions: molecular mechanisms of RBR ubiquitin ligases

Cotton

Lechtenberg

2020

Biochemical Society Transactions

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“…A substantial amount of HOIL-1L in LUBAC is modified post-translationally [46], and modification of HOIL-1L disappears when HOIL-1L E3 activity is lost. We then dissected the roles of HOIL-1L E3 played in LUBAC function and found that loss of HOIL-1L E3 function promotes LUBAC-mediated NF-jB activation and suppression of programmed cell death [47]. Based on these findings, we explored the molecular mechanism underlying the suppression of LUBAC function by the HOIL-1L E3.…”

Section: Regulatory Mechanism Of Lubacmediated Linear Ubiquitinationmentioning

confidence: 99%

“…Based on these findings, we explored the molecular mechanism underlying the suppression of LUBAC function by the HOIL-1L E3. The results can be summarized as follows [47]: HOIL-1L monoubiquitinates HOIL-1L as well as HOIP and SHARPIN, and the monoubiquitinated LUBAC subunits are recognized by HOIP to generate linear chains. Monoubiquitin conjugated onto LUBAC subunits by HOIL-1L renders the subunits to the suitable substrate for HOIP because HOIP specifically recognizes acceptor ubiquitin moieties with a linear ubiquitin chain-determining (LDD) domain and conjugates the donor ubiquitin onto the N terminus of the acceptor ubiquitin to form linear ubiquitin chains [48,49].…”

Section: Regulatory Mechanism Of Lubacmediated Linear Ubiquitinationmentioning

confidence: 99%

“…Thus, loss of HOIL-1L E3 activity promotes LUBAC function by suppressing the modification of LUBAC by linear ubiquitination. A HOIL-1L mutant lacking E3 activity improves cpdm dermatitis, which is caused by reduced amounts of the LUBAC complex composed of HOIL-1L and HOIP, and protects cells against Salmonella infection [47].…”

Section: Regulatory Mechanism Of Lubacmediated Linear Ubiquitinationmentioning

confidence: 99%

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Discovery of linear ubiquitination, a crucial regulator for immune signaling and cell death

Iwaï

2020

The FEBS Journal

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Ubiquitination is a reversible post-translational modification that regulates function of conjugated proteins by decorating with ubiquitin chains-polymer of ubiquitin-in most cases. The discovery of linear ubiquitin chains and the linear ubiquitin chain assembly complex (LUBAC) ubiquitin ligase complex can be considered as paradigm shift in the ubiquitin research because the linear ubiquitin chain is generated via the N-terminal Met of ubiquitin, although the other ubiquitin chains are generated via one of seven Lys residues in ubiquitin. Moreover, ubiquitination is distributed throughout eukaryotic kingdoms; however, no linear ubiquitination could be found in lower eukaryotes including yeasts. Although the involvement of ubiquitination in proteolysis is well-documented, linear ubiquitination plays crucial roles in immune signaling and cell death regulation. Moreover, dysregulation of LUBAC-mediated linear ubiquitination underlies various human diseases including autoinflammation and cancer. Here, I introduce how linear ubiquitination was discovered and outline a brief history of linear ubiquitination research.

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“…All members of the LUBAC have been reported to carry linear ubiquitin chains through auto-ubiquitination [23,24]. Recently, Iwai and colleagues demonstrated that HOIL-1 E3 ligase mono-ubiquitinates the LUBAC, which causes HOIP to preferentially decorate the LUBAC with linear ubiquitin chains rather than other substrates [25]. Linear auto-ubiquitination of the LUBAC can be removed by the OTU deubiquitinase with linear linkage specificity (OTULIN) [23,24].…”

Section: Introductionmentioning

confidence: 99%

Serine 165 Phosphorylation of SHARPIN regulates the Activation of NF-κB

Thys

Trillet

Rosińska

et al. 2020

Preprint

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AbstractThe adaptor SHARPIN composes, together with the E3 ligases HOIP and HOIL1, the linear ubiquitin chain assembly complex. This enzymatic complex catalyzes and stamps atypical linear ubiquitin chains onto substrates to modify their fate, and has been linked to the regulation of the NF-κB pathway downstream most immunoreceptors, inflammation and cell death. However, how this signaling complex is regulated is not fully understood. Here, we report that a portion of SHARPIN is constitutively phosphorylated on the serine in position 165 in lymphoblastoid cells, and can be further induced following antigen receptor stimulation. Analysis of a phosphorylation-resistant mutant of SHARPIN revealed that this mark is dispensable for the generation of linear ubiquitin chains. However, phosphorylation allows the optimal activation of NF-κB in response to TNFα and T-cell receptor engagement. These results identify a new layer of regulation of the LUBAC, and unveil new strategies to modulate its action.

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The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC

Cited by 78 publications

References 63 publications

Chain reactions: molecular mechanisms of RBR ubiquitin ligases

Chain reactions: molecular mechanisms of RBR ubiquitin ligases

Discovery of linear ubiquitination, a crucial regulator for immune signaling and cell death

Serine 165 Phosphorylation of SHARPIN regulates the Activation of NF-κB

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