ITCH

Description

The ITCH (itchy E3 ubiquitin protein ligase) is a protein-coding gene located on chromosome 20.

ITCH is a HECT domain–containing E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H (aka Itchy) mice. Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation. In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function. The ITCH gene is located on chromosome 20 in humans. ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.

== Regulation by phosphorylation == ITCH is regulated by MAPK8. MAPK8 regulates JUNB protein turnover by MAPK8-dependent phosphorylation of ITCH and a subsequent conformational change in ITCH. This mechanism is discrete from the direct activation of Jun family transcription factors by direct phosphorylation. ITCH serves as a paradigm for our understanding of the regulation of the ubiquitylation machinery by direct protein phosphorylation of its components. Importantly, this regulatory process controls the balance of Th2 cytokine secretion by negatively regulating JUNB levels and Interleukin 4 transcription.

== Interaction partners == Itch has been shown to interact with a number of proteins, including:

CXCR4, c-Jun, MAP2K4, MAP3K1, MAP3K7, MAPK8, N4BP1, NOTCH1, TP63, and TP73.

ITCH acts as an E3 ubiquitin ligase, a type of enzyme that attaches ubiquitin molecules to other proteins. It receives ubiquitin from another enzyme, E2 ubiquitin-conjugating enzyme, and transfers it to specific target proteins. ITCH can catalyze the formation of different types of ubiquitin chains, including Lys-29-, Lys-48-, and Lys-63-linked chains. These chains are involved in various cellular processes, including protein degradation, signaling, and trafficking. ITCH plays a crucial role in the control of inflammatory signaling pathways by being a component of a ubiquitin-editing complex that includes TNFAIP3, TAX1BP1, and RNF11. This complex ensures that inflammatory signaling is transient by promoting the degradation of key signaling molecules, such as RIPK1. ITCH also ubiquitinates other proteins, including RIPK2, MAVS, and NFE2, influencing various cellular functions, such as immune responses, antiviral signaling, and hematopoiesis. ITCH also regulates the activity of several transcription factors, including JUNB, which is important for the regulation of type 2 helper T cell (Th2) cytokine production. Furthermore, ITCH is involved in the sorting of proteins to the degradative endocytic pathway, such as the Wnt receptor FZD4 and chemokine receptor CXCR4. It also controls the degradation of other proteins, including DTX1, NOTCH1, and NEDD9/HEF1.

ITCH is also known as ADMFD, AIF4, AIP4, NAPP1.

Associated Diseases

• Autoimmune disease, multisystem, with facial dysmorphism
• Syndromic multisystem autoimmune disease due to Itch deficiency