OTULIN deficiency: focus on innate immune system impairment

Abstract

OTULIN deficiency is a complex disease characterized by a wide range of clinical manifestations, including skin rash, joint welling, lipodystrophy to pulmonary abscess, and sepsis shock. This disease is mechanistically linked to mutations in the OTULIN gene, resulting in an immune disorder that compromises the body's ability to effectively combat pathogens and foreign stimuli. The OTULIN gene is responsible for encoding a deubiquitinating enzyme crucial for hydrolyzing Met1-poly Ub chains, and its dysfunction leads to dysregulated immune responses. Patients with OTULIN deficiency often exhibit an increase in monocytes, including neutrophils and macrophages, along with inflammatory clinical features. The onset of symptoms typically occurs at an early age. However, individuals with OTULIN haploinsufficiency are particularly susceptible to life-threatening staphylococcal infections. Currently, the most effective treatment for patients with OTULIN biallelic mutations involves the use of TNF-blocking agents, which target the dysregulated immune response. In conclusion, OTULIN deficiency presents a complex clinical picture with diverse manifestations, attributed to mutations in the OTULIN gene. Understanding the underlying mechanisms is crucial for developing targeted therapeutic interventions to address this challenging condition. Further research into the pathophysiology of OTULIN deficiency is essential for improving clinical management and outcomes for affected individuals.

Keywords: OTULIN; autoinflammatory disorder; deubiquitinase; genetic deficiency; immunodeficient disorder.

Figure 1

Domain organization of OTU deubiquitinates. (A) Schematic figure of the domain structures and important residues. The N-terminus of OTULIN contains the PUB-interaction motif (PIM) that mediates the interaction with the HOIP subunit of LUBAC. The OTU domain contains a catalytic triad consisting of Cys129, His339, and Asn342. The C-terminal OTULIN domain contains a PD2 binding motif (PDZbm) responsible for binding to the snx27. Gly174, Tyr244, Leu272, or Gly281 mutations in OTULIN catalytically inactivate OTULIN or reduce protein stability causing the severe inflammatory phenotype in ORAS patients. (B) Structure of OTULIN (green) bound to the Met1-linked Di-ubiquitin activating probe (brown) with a close-up view of the catalytic triad (Cys129, His339, and Asn341). Image created with Biorender.com.

Figure 2

Clinical features of OTULIN with biallelic hypomorphic mutations. Image created with Biorender.com.