*2.7. Autoimmune Disorder*

Mutations in the HECT-domain E3 ligase Itchy (ITCH) are found in a rare form of autoimmune disorder associated with facial dysmorphism, organomegaly, and developmental delay (Table 1). These patients also present severe autoimmune inflammatory cell infiltration of the lungs, liver, and gu<sup>t</sup> [80]. Genetic analysis of the patients identified homozygosity for a frameshift mutation of *ITCH* caused by a 1-bp insertion, resulting in a truncated protein [80]. Mice lacking expression of the *Itch* gene develop a wide spectrum of immunologic phenotypes, such as lung and stomach inflammation, as well as hyperplasia of lymphoid cells and itching [116]. *Itch* deficiency in mice also renders mice resistant to TNF α-induced acute liver failure [117].

Di fferent mechanisms have been proposed for the role of ITCH in human pathogenesis. ITCH was shown to regulate the stability and subcellular localization of multiple targets by mediating not only poly-ubiquitination, but also monoubiquitnation. ITCH-mediated monoubiquitination promotes degradation of the key regulators of T-cell anergy, phospholipase C-γ1 (PLC-γ1) and protein kinase C-theta (PKC-θ) [118]. ITCH can also suppress inflammation by controlling ubiquitination of tumor necrosis factor alpha-induced protein 3 (TNFAIP3, also called A20) [119]. Moreover, in T cells, ITCH mediates monoubiquitination of TGF-β inducible early gene-1 (TIEG1) [78]. Monoubiquitinated TIEG1 is translocated to the nucleus and triggers expression of Forkhead Box P3 (FOXP3), a master regulator of T cell function (Treg cells). *Tieg1* deficient mice are not able to suppress lung inflammation, indicating that deficiency in TIEG1 ubiquitination can explain ITCH-mediated pathogenesis in patients with autoimmune disorder.

Furthermore, ITCH regulates subcellular localization of survival motor neuron (SMN) by mediating its monoubiquitination [79]. Specifically, SMN is expressed mainly in the nucleus, where it accumulates in subnuclear structures such as the Cajal body. Dysregulation of SMN ubiquitination significantly impairs its co-localization with small nuclear ribonucleoprotein (snRNP) in Cajal body foci [79]. Importantly, SMN loss of function causes spinal muscular atrophy, a neuromuscular disease characterized by motor neurons degeneration, suggesting that the ITCH/SMN axis might be a major driver of muscular atrophy and dysmorphism (Figure 1E).
