Neuronal cilia have emerged as crucial signaling hubs, yet their molecular composition and integration with synaptic communication remain poorly understood. Using a newly developed Arl13b-TurboID mous...

The temporospatial distribution of proteins within cilia is regulated by intraflagellar transport (IFT), wherein molecular trains shuttle between the cell body and cilium. Defects in this process impair various signal-transduction pathways and cause ciliopathies. Although K63-linked ubiquitination appears to trigger protein export from cilia, the mechanisms coupling polyubiquitinated proteins to IFT remain unclear. Using a multidisciplinary approach, we demonstrate that a complex of CFAP36, a conserved ciliary protein of previously unknown function, and ARL3, a GTPase involved in ciliary import, binds polyubiquitinated proteins and links them to retrograde IFT trains. CFAP36 uses a coincidence detection mechanism to simultaneously bind two IFT subunits accessible only in retrograde trains. Depleting CFAP36 accumulates K63-linked ubiquitin in cilia and disrupts Hedgehog signaling, a pathway reliant on the retrieval of ubiquitinated receptors. These findings advance our understanding of ubiquitin-mediated protein transport and ciliary homeostasis, and demonstrate how structural changes in IFT trains achieve cargo selectivity. ### Competing Interest Statement The authors have declared no competing interest. Sara Elizabeth O'Brien Trust Postdoctoral Fellowship awarded through the Charles A. King Trust Postdoctoral Research Fellowship Program, , 8460873-01 Richard and Susan Smith Family Foundation, https://ror.org/05j95n956, National Institute of General Medical Sciences (NIGMS), , R01GM141109, R01GM143183

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The authors show that protein TFG self-organizes to form a hollow sphere that helps to guide and spatially organize bidirectional transport at a critical junction between the ER and Golgi in the early...

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The climate crisis is a multiscale problem that requires transdisciplinary expertise for understanding and engineering climate resilience. Cells are the first responders of the biosphere and yet cell…

The melanocortin receptor 4 (MC4R) regulates body weight homeostasis at the cilium of hypothalamic neurons, but its levels are very low under unrestricted feeding conditions. Here, the authors find th...

MC4R colocalizes with ADCY3 at primary cilia in hypothalamic neurons, and MC4R mutations associated with human obesity impair this localization. Inhibition of adenylyl cyclase signaling at primary cil...

image image Rab35 at the mammalian and zebrafish cilium regulates cilium length and left‐right asymmetry, and controls the ciliary levels of PI(4,5)P2 and regulators of the Sonic hedgehog pathway. Rab35 GTPase localizes to the ciliary ...