Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Differential Roles of Tubby Family Proteins in Ciliary Formation and Trafficking

  • Hong, Julie J. (Department of Oral Biology, BK 21 FOUR Project, Yonsei University College of Dentistry) ;
  • Kim, Kyung Eun (Department of Oral Biology, BK 21 FOUR Project, Yonsei University College of Dentistry) ;
  • Park, So Young (Department of Oral Biology, BK 21 FOUR Project, Yonsei University College of Dentistry) ;
  • Bok, Jinwoong (Department of Anatomy, Yonsei University College of Medicine) ;
  • Seo, Jeong Taeg (Department of Oral Biology, BK 21 FOUR Project, Yonsei University College of Dentistry) ;
  • Moon, Seok Jun (Department of Oral Biology, BK 21 FOUR Project, Yonsei University College of Dentistry)
  • Received : 2021.04.07
  • Accepted : 2021.06.02
  • Published : 2021.08.31
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Abstract

Cilia are highly specialized organelles that extend from the cell membrane and function as cellular signaling hubs. Thus, cilia formation and the trafficking of signaling molecules into cilia are essential cellular processes. TULP3 and Tubby (TUB) are members of the tubby-like protein (TULP) family that regulate the ciliary trafficking of G-protein coupled receptors, but the functions of the remaining TULPs (i.e., TULP1 and TULP2) remain unclear. Herein, we explore whether these four structurally similar TULPs share a molecular function in ciliary protein trafficking. We found that TULP3 and TUB, but not TULP1 or TULP2, can rescue the defective cilia formation observed in TULP3-knockout (KO) hTERT RPE-1 cells. TULP3 and TUB also fully rescue the defective ciliary localization of ARL13B, INPP5E, and GPR161 in TULP3 KO RPE-1 cells, while TULP1 and TULP2 only mediate partial rescues. Furthermore, loss of TULP3 results in abnormal IFT140 localization, which can be fully rescued by TUB and partially rescued by TULP1 and TULP2. TUB's capacity for binding IFT-A is essential for its role in cilia formation and ciliary protein trafficking in RPE-1 cells, whereas its capacity for PIP2 binding is required for proper cilia length and IFT140 localization. Finally, chimeric TULP1 containing the IFT-A binding domain of TULP3 fully rescues ciliary protein trafficking, but not cilia formation. Together, these two TULP domains play distinct roles in ciliary protein trafficking but are insufficient for cilia formation in RPE-1 cells. In addition, TULP1 and TULP2 play other unknown molecular roles that should be addressed in the future.

Keywords

Acknowledgement

This work was supported by National Research Foundation of Korea (NRF) Grants funded by the Korean Government (NRF-2016R1A5A2008630 and NRF-2018R1A2B3001668).

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