Unknown

Dataset Information

0

Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling.


ABSTRACT: Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP. Here, we show that HOIL-1L ΔRING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sjögren's syndrome in a female-dominant fashion. Augmented LUBAC activity led to hyperactivation of both lymphoid and myeloid cells. In line with the findings in mice, we sought to identify missense single nucleotide polymorphisms/variations of the RBCK1/HOIL-1L gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the RBCK1/HOIL-1L gene, attenuated HOIL-1L ligase activity and augmented LUBAC-mediated immune signaling, including that mediated by Toll-like receptors. We also found that rs774507518 was enriched significantly in patients with SLE, strongly suggesting that RBCK1/HOIL-1L is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease.

SUBMITTER: Fuseya Y 

PROVIDER: S-EPMC10967397 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling.

Fuseya Yasuhiro Y   Kadoba Keiichiro K   Liu Xiaoxi X   Suetsugu Hiroyuki H   Iwasaki Takeshi T   Ohmura Koichiro K   Sumida Takayuki T   Kochi Yuta Y   Morinobu Akio A   Terao Chikashi C   Iwai Kazuhiro K  

JCI insight 20240208 3


Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, au  ...[more]

Similar Datasets

| S-EPMC8561004 | biostudies-literature
| S-EPMC10575588 | biostudies-literature
| S-EPMC10511788 | biostudies-literature
| S-EPMC3251058 | biostudies-literature
| S-EPMC9016349 | biostudies-literature
| S-EPMC1618115 | biostudies-literature
| S-EPMC3639560 | biostudies-other
| S-EPMC6613137 | biostudies-literature
| S-EPMC2833372 | biostudies-literature
| S-EPMC3403446 | biostudies-literature