ITCH

Cilia effects upon perturbation of ITCH

Ciliogenesis screen results (4 screens)

• Kim2016: Not Reported
• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-4.60) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: Positive Regulator (Hh signaling, casTLE effect=-1.64) PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381

Phenotypes

Mouse phenotype:

increased spleen weight, increased lymphocyte cell number, decreased bone mineral content, increased circulating calcium level, increased large unstained cell number, decreased hematocrit, increased leukocyte cell number, decreased mean corpuscular hemoglobin, decreased total body fat amount, tremors, decreased exploration in new environment, enlarged spleen, decreased bone mineral density, abnormal tooth morphology, decreased hemoglobin content, increased circulating amylase level, increased blood urea nitrogen level, abnormal esophagus morphology, increased basophil cell number, decreased fasting circulating glucose level, decreased circulating fructosamine level, decreased mean corpuscular volume, increased eosinophil cell number, increased neutrophil cell number, increased red blood cell distribution width, increased circulating phosphate level, decreased circulating alkaline phosphatase level, decreased lymphocyte cell number, increased circulating total protein level, abnormal startle reflex, decreased circulating glucose level, abnormal head size, increased mean corpuscular volume, enlarged gallbladder, increased lean body mass, abnormal bone structure

Mouse ciliopathy phenotype:

enlarged kidney, increased circulating aspartate transamise level, increased heart weight

Subcellular localization

basal body, cytosol, endosome, nucleus

Functional category

• Ciliary assembly/disassembly
• Trafficking (BBSome, small GTPases, vesicular transport, ATPases)
• Actin & cytoskeleton regulation
• T cell biology
• Viral interactions
• Cell migration & adhesion
• Signaling (Hedgehog, GPCRs, ion channels)
• Transcription regulation

Function

ITCH plays a key regulatory role in cilium-based Hedgehog sig ling by controlling the degradation and trafficking of PTCH1, a cilia-localized receptor ( 25092867). ALIX, a protein previously linked to the biogenesis of small extracellular vesicles, as a novel component localized at the base of primary cilia in cultured mammalian cells. We show that ALIX retention at this site requires the ciliary kinesin-3 motor protein KIF13B, which physically interacts with ALIX and the E3 ubiquitin ligase ITCH. In turn, ITCH is enriched at the ciliary base and is essential for ALIX stability. Depletion of either ALIX or ITCH results in elevated ciliary levels of Polycystin-2, while ITCH loss additionally leads to constitutive accumulation of Smoothened, a key Sonic hedgehog effector, within the cilium. Collectively, our findings establish ALIX and ITCH as critical regulators of ciliary membrane protein homeostasis and signaling, acting in coordination with KIF13B to maintain proper ciliary function(PMID: 41742018).