TNIP1/ABIN1 and lupus nephritis: review

Abstract

SLE is a complex autoimmune disease with genetic, epigenetic, immune-regulatory, environmental and hormonal factors. Kidney inflammation and injury, termed lupus nephritis (LN), occurs in over half of patients with SLE and is a leading cause of disability and death. There is a high degree of short-term and long-term side effects associated with current LN therapies and they are not effective for many patients. Thus, novel therapies with reduced toxicity and improved efficacy are drastically needed. Many of the known LN susceptibility genes have functions that mediate inflammation via cytokine/chemokine production and activation of myeloid and B cells. Understanding the cellular and molecular mechanisms mediated by these variant gene products provides valuable insight for the development of improved and personalised diagnostics and therapeutics. This review describes variants in the TNIP1 (tumour necrosis factor α-induced protein 3-interacting protein 1) gene associated with risks for SLE and LN and potential roles for loss of function of its protein product ABIN1 in the activation of myeloid and B-cell-mediated injury in LN.

Prevention and partial reversion of the lupus phenotype in ABIN1[D485N] mice by an IRAK4 inhibitor

“…ABIN1 (A20-binding inhibitor of NF-κB 1) is a polyubiquitin-binding protein that restricts the production of inflammatory mediators by the innate immune system. Polymorphisms in TNIP1 , the gene encoding ABIN1, predispose to lupus in many human populations (reviewed, 1 ), and mice deficient in ABIN1 2 or expressing a polyubiquitin-binding-deficient mutant of ABIN1 (ABIN1[D485N]) 3 develop a disease resembling type III/IV human lupus nephritis. 4 All the major facets of lupus in ABIN1[D485N] mice can be prevented by crossing ABIN1[D485N] mice to mice expressing the kinase-inactive IRAK4[D329A] mutant 5 or by oral administration of the small molecule IRAK4 inhibitor PF 06426779 prior to the appearance of the hallmark features of lupus, such as glomerulonephritis, liver and lung inflammation, and increased levels of autoantibodies.…”

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

“…In addition to splenomegaly and lymphadenopathy, HOIL-1L ∆RING1 mice exhibited elevated serum immunoglobulins ( Figure 2, A–C , and Supplemental Figure 2A ), a phenomenon often observed in patients with SLE. Therefore, we asked whether HOIL-1L ∆RING1 mice exhibit lupus-like symptoms, including lupus nephritis ( 1 , 2 , 27 ). Histopathologic assessment revealed proliferation of mesangial cells, with deposition of IgG and complement components C3 and C1q (all characteristic features of lupus nephritis) in the glomerulus of 7-month-old HOIL-1L ΔRING1/ΔRING1 female mice ( Figure 2, D and E , and Supplemental Figure 2, B and C ).…”

“…The first is TNIP1/ABIN1 ( 27 , 51 ). SLE susceptibility SNPs in TNIP1/ABIN1 augment linear ubiquitination by reducing expression of ABIN1 ( 9 , 26 , 27 , 50 , 51 ); this is because ABIN1 suppresses LUBAC functions acting as a linear chain-specific autophagy adaptor ( 13 ). Another gene is UBE2L3 ( 9 , 49 , 50 , 52 , 53 ).…”

Lupus Nephritis and Dysbiosis

“…The etiology of SLE and LN is very complex and may be a result of the interplay between genetic susceptibility and hormonal and environmental factors, including infections and dysbiosis [ 2 ]. Many of the known LN susceptibility genes are responsible for mediating inflammation via cytokine/chemokine production and the activation of myeloid and B cells [ 3 ]. Some of the genes are related to bacterial responses, such as the mannose-binding lectin 2 (MBL2) gene.…”