Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins.
The primary cilium is a paradigmatic organelle for studying compartmentalized signaling; however, unlike soluble protein trafficking, processes targeting integral membrane proteins to cilia are poorly understood. In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. The founding tubby family member TUB also localizes to cilia similar to TULP3 and determines trafficking of a subset of these GPCRs to neuronal cilia. Using minimal ciliary localization sequences from GPCRs and fibrocystin (also implicated in polycystic kidney disease), we demonstrate these motifs to be sufficient and TULP3 dependent for ciliary trafficking. We propose a three-step model for TULP3/TUB-mediated ciliary trafficking, including the capture of diverse membrane cargo by the tubby domain in a phosphoinositide 4,5-bisphosphate (PI(4,5)P2)-dependent manner, ciliary delivery by intraflagellar transport complex A binding to the TULP3/TUB N terminus, and subsequent release into PI(4,5)P2-deficient ciliary membrane.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 saikat.mukhopadhyay@utsouthwestern.edu hemant.badgandi@utsouthwestern.edu.
Hemant B
0000-0001-6181-4241
HB
Badgandi
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Sun-Hee
0000-0001-6060-8710
SH
Hwang
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Issei S
IS
Shimada
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|STARS Program, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Jesuit College Preparatory School of Dallas, Dallas, TX 75244.
Evan
E
Loriot
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 saikat.mukhopadhyay@utsouthwestern.edu hemant.badgandi@utsouthwestern.edu.
Saikat
0000-0003-4790-3090
S
Mukhopadhyay
D000818:Animals; D002460:Cell Line; D002923:Cilia / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010716:Phosphatidylinositols / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000378:metabolism
D008565:Membrane Proteins; D010716:Phosphatidylinositols; D043562:Receptors, G-Protein-Coupled; D050396:TRPP Cation Channels