ITCH Gene

The ITCH gene (ITCH stands for "Itchy E3 Ubiquitin Protein Ligase") is a protein-coding gene located on chromosome 20q11.22. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

The ITCH gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, targeting specific proteins for lysosomal degradation. The encoded protein plays a role in numerous cellular processes, including erythroid and lymphoid cell differentiation and regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune diseases (see ITCH E3 ubiquitin ligase deficiency below).

The encoded protein acts as an E3 ubiquitin-protein ligase that accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to the target substrates. Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. Itchy E3 ubiquitin protein ligase is involved in the control of inflammatory signaling pathways. The enzyme is an essential component of a ubiquitin-modifying protein complex that also includes TNFAIP3, TAX1BP1, and RNF11, which provides control of inflammatory signaling pathways. Promotes association of the complex after TNF stimulation (PubMed:19131965). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains at RIPK1 and catalyzes the formation of 'Lys-48' polyubiquitin chains. This leads to proteasomal degradation of RIPK1 and consequently termination of TNF- or LPS-mediated activation of NFKB1.

ITCH ubiquitinates RIPK2 through 'Lys-63'-linked conjugation and affects NOD2-dependent signal transduction pathways. It regulates the transcriptional activity of several transcription factors and likely plays an important role in regulating the immune response. ITCH inhibits influenza A virus (IAV) replication by ubiquitination of IAV matrix protein 1 (M1) via 'Lys-48'-linked conjugation, leading to proteasomal degradation of M1.

Diseases associated with ITCH include syndromic multisystem autoimmune diseases and Itch E3 ubiquitin ligase deficiency syndrome.

1. Moser EK et al (2019) Regulation of autoimmune disease by the E3 ubiquitin ligase Itch. Cell Immunol 340:103916.
2. Wang A et al. (2019) Regulation of T cell differentiation and function by ubiquitin-specific proteases. Cell Immunol 340:103922.