The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity

Abstract

SummaryMethionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.

OTULIN deficiency causes auto-inflammatory syndrome

“…This led to severe weight loss in the mice accompanied by increased neutrophil infiltration and elevated serum levels of cytokines and chemokines. Strikingly, treating mice with anti-TNF, like in the ORAS patients, rescued most disease symptoms [9].…”

“…Additionally, OTULIN-deficient BMDMs displayed features of elevated baseline activity of NF-κB signaling, which was not reduced by TNF-blocking antibodies. This implies that loss of OTULIN in BMDMs causes enhanced cell-autonomous NF-κB signaling, possibly triggered by the accumulation of Met1-Ub [9].…”

“…Interestingly, analysis of mice where OTULIN was ablated in T-cells, B-cells or in myeloid cells showed that ablation of OTULIN in B-and T-cells caused no overt phenotype whereas mice that lacked OTULIN in myeloid cells displayed enlarged lymphoid organs and liver, had immune cell infiltration in the liver, and increased cytokine levels in serum [9]. While this suggests that lymphoid cells rely less on OTULIN for NF-κB pathway regulation than myeloid cells, this is unexpected since previous studies have found that mutations affecting LUBAC activity profoundly impact B-and T-cell function [1].…”

“…Damgaard et al [9] now reveal that a loss-of-function mutation in OTULIN leads to an early-onset autoinflammatory disease termed ORAS (OTULINrelated autoinflammatory syndrome). The study identifies a homozygous missense mutation in OTULIN (c.815T>C; p.Leu272Pro) in three affected individuals from a consanguineous family.…”

“…Accordingly, isolated white blood cells from an ORAS patient exhibited elevated Met1-Ub levels as compared to healthy donor cells. ORAS patients presented with early-onset and severe systemic inflammation that can be managed with anti-TNF treatment [9].…”