New roles for TBC1D20 a Rab-GAP modulating ER-to-Golgi trafficking

TBC1D20 is a Rab1-GAP that modulates intracellular trafficking and Golgi biogenesis. However, the exact role of TBC1D20 in intracellular trafficking is still unknown. We hypothesize that TBC1D20 has a role in regulating cargo accumulation. Indeed, our preliminary results show increased microtubule-uncoupled cargo-protein sorting in brefeldin A-nocodazole treated TBC1D20 null fibroblasts compared to controls.

Warburg Micro Syndrome (WARBM) is an autosomal recessive disorder causing severe mental retardation,microcephaly, microcornea, congenital cataract and optic atrophy. Loss of function mutations in TBC1D20 as well as Rab18 and Rab3GAP1 were found to underlie WARBM. Lipid droplets (LDs) are regulated neutral lipid storage organelles having a central role in numerous cellular processes as well as in various pathologies. We have previously found that a hepatitis C virus protein NS5A binds TBC1D20 and recruits TBC1D20 and Rab1 to contracts sites between the endoplasmic reticulum and LDs. We found that a subfraction of Rab1, associates with LDs and overexpression of its dominant-negative form, significantly reduced LD number. Interestingly TBC1D20 null fibroblasts from WARBM patients and mice models display abnormally large LDs, further linking Rab1 to LD metabolism. The majority of WARBM TBC1D20 mutations are nonsense mutations generating an inactivated protein. Various drugs were previously found to decode premature termination codons and restore the functions of the protein. Thus, we employ this strategy for correcting the function of TBC1D20 and offer new insights into the role of TBC1D20 and Rab1.