Cellular Switches in Ciliopathies

Small GTPases function as molecular switches in diverse membrane- and cytoskeleton-related cellular processes, alternating between inactive GDP- and active GTP-bound states. Small GTPases are switched on by guanine nucleotide exchange factors (GEFs) and off by GTPase activating proteins (GAPs).

The unique features of small GTPases have made them and their effectors favorable therapeutic targets in many human diseases. The family of mammalian ARF and ARL GTPases includes 29 members, but the in vivo roles and regulators (GEF, GAP and effectors) of most ARFs/ARLs are poorly defined. A comparative genomics study revealed that Arl3 and Arl6 are present only in ciliated organisms. Mutations in ARL3 or ARL13B cause the classical form of Joubert's syndrome. Arl3-/- and Arl13b-/- mice exhibit typical ciliopathy manifestations. Human ARL6 has been identified as BBS3, one of the loci involved in the ciliopathy Bardet-Biedl syndrome. This suggests that the ciliary ARLs play decisive roles in the context of cilia.

Dr. Hu's research team aims to determine the function and regulators of the ARLs, with the ultimate goal to identify novel and actionable therapeutic targets to prevent, delay or halt ciliopathy progression.