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IFT172, the largest protein of the IFT complex, plays a crucial role in cilium formation, and several disease-causing IFT172 variants have been identified in ciliopathy patients. While IFT172 is tethered to the IFT-B complex via its N-terminal domains, the function of its C-terminal domains has remained elusive. Here, using both human and\n                    <jats:italic>Chlamydomonas reinhardtii<\/jats:italic>\n                    IFT172, we reveal that the C-terminal part of IFT172 interacts with IFT-A complex subunits, providing a molecular basis for the role of IFT172 in bridging IFT-A and IFT-B complexes. We determine the crystal structure of the C-terminal part of IFT172, uncovering a conserved U-box-like domain often found in E3 ubiquitin ligases. This domain exhibits ubiquitin-binding properties, and IFT172 undergoes ubiquitin conjugation in vitro, an activity that is reduced in the C1727R patient ciliopathy variant. We use CRISPR-engineered RPE-1 cells to demonstrate that the U-box-like domain is essential for IFT172 protein stability and proper cilium formation. Notably, RPE-1 cells with heterozygous deletion of the U-box domain show altered TGF-\u03b2 signaling responses, particularly in SMAD2 phosphorylation levels and AKT activation. Our findings suggest that IFT172, beyond its structural role in bridging IFT-A and IFT-B complexes within IFT trains, harbors a conserved U-box-like domain with potential involvement in ciliary ubiquitination processes and signaling, providing new insights into the molecular mechanisms underlying IFT172-related ciliopathies.\n                  <\/jats:p>","DOI":"10.7554\/elife.104906","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T11:25:56Z","timestamp":1738322756000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.104906","source":"Crossref","is-referenced-by-count":0,"title":["Intraflagellar transport protein IFT172 contains a C-terminal ubiquitin-binding U-box-like domain involved in ciliary signaling"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2613-2610","authenticated-orcid":true,"given":"Nevin 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