OTULIN Gene

The OTULIN gene (OTULIN stands for "OTU Deubiquitinase With Linear Linkage Specificity") is a protein-coding gene located on chromosome 5p15.2. The OTULIN gene encodes a member of the peptidase C65 family of ubiquitin isopeptidases. Members of this family remove ubiquitin from proteins. The encoded enzyme specifically recognizes and removes M1(Met1)-linked or linear ubiquitin chains from protein substrates. Linear ubiquitin chains are known to regulate the NF-kappa-B signaling pathway in the context of immunity and inflammation.

OTULIN deubiquitinase, which specifically removes linear ('Met-1'-linked) polyubiquitin chains on substrates acts as a regulator of angiogenesis and innate immune response. The encoded protein is required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling pathway together with the LUBAC complex. The function of OTULIN is mainly restricted to the homeostasis of the LUBAC complex.

The encoded protein acts as an important negative regulator of inflammation by limiting spontaneous inflammation and maintaining immune homeostasis. In myeloid cells, it is required to prevent excessive secretion of cytokines that lead to inflammation and autoimmunity.

Mutations in this gene lead to a potentially fatal autoinflammatory syndrome in humans.

Diseases associated with OTULIN include:

• autoinflammation, panniculitis and dermatosis syndrome
• and
• craniometaphyseal dysplasia, autosomal dominant.

1. Damgaard RB et al. (2016) The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell 166: 1215-1230.
2. Hoste E et al (2021) OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity. Nat Commun 12:5913.
3. Zhou A et al (2016) Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Nat Acad Sci 113: 10127-10132.