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

自己免疫疾患の発症メカニズムの一端を解明 --自己免疫疾患の新規治療ターゲットへ--. 京都大学プレスリリース. 2024-02-09.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

Effect of tank shape on survival and growth of Pacific bluefin tuna Thunnus orientalis larvae

We examined the effect of rearing tank shape on survival and growth of Pacific bluefin tuna Thunnus orientalis larvae. Cylindrical (1.7 × 103 cm2 water surface area; 30 cm deep) and rectangular (1.8 × 103 cm2 water surface area; 28 cm deep) tanks (n = 3 each) were filled with 50 l of seawater. One air stone with a 100 ml/min aeration rate was set at the bottom center of each tank. Light intensity at the water surface was 2000 lx with a photoperiod of 24 L:0D. Larvae were introduced into each tank at a rate of 10 individuals/l at 2 days post-hatching (dph). Rotifers were fed at 10 individuals/ml and their distribution in tanks was measured. Survival of larvae in cylindrical tanks (CT; 52.7 ± 5.1%) at 8 dph was higher than that in rectangular tanks (RT; 0.8 ± 0.7%, p < .01). Meanwhile, larvae growth was not significantly different between tank shapes either in body length (CT: 4.23?±?0.26?mm; RT: 4.09 ± 0.20 mm) or dry weights (CT: 95.1 ± 17.6 μg; RT: 67.7 ± 10.9 μg). The swimbladder inflation rate of larvae also did not differ significantly between tank shapes (CT: 16.5 ± 14.5%; RT: 56.9 ± 3.47%). Rotifer distribution was higher at tank bottom in both shapes (p < .05). Two-phase bubbly flow simulations in the tanks revealed that the low-flow area was larger in the RT. The low-flow area at tank bottom varied by tank shape, occurring at the edge of the tank wall on the bottom in the CT, and from the center of the tank (air stone) to the tank wall in the RT. These low-flow areas at tank bottom coincided with areas of higher rotifer distribution, which may be a cause of sinking syndrome in fish larvae. Our results indicate that small-scale (50-l) PBT larviculture experiments can be conducted using a CT with the present aeration system, and that an RT requires an improved aerator in place of the single air stone

A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10−9, odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4+ and CD19+ peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset