Rab38, Varp and VAMP7 interactions define a biased trafficking pathway in lung alveolar type II cell

We have reported that Rab38, a rat Hermansky‐Pudlak Syndrome (HPS) protein, targets to ~30 % lamellar bodies (LBs) in alveolar type II (ATII) pneumocyte; importantly, Rab38 reexpression in cultured ATII cells isolated from the Rab38‐null Fawn‐hooded hypertension (FHH) rat lungs rescues the giant LB pathology of HPS (Zhang et al. , 2011, AJP Lung Cell. Mol. Physiol.). In this study, we demonstrate a biased trafficking pathway mediated by Rab38 interaction with its downstream effecter Varp, which preferentially recruits VAMP7‐positive vesicles to Rab38‐labeled LBs. When expressed alone in cultured FHH ATII cells, mStrawberry (mStr) tagged Varp was predominantly found in cytosol. In contrast, when coexpressed with EGFP‐Rab38, mStr‐Varp was dramatically recruited to Rab38‐positive LB surfaces. EGFP‐VAMP7 labeled both LB limiting membranes and vesicular compartments in cultured ATII cells; coexpressing EGFP‐VAMP7 and str‐Varp similarly localized the latter molecule to VAMP7‐positive LB and vesicle surfaces. These results indicate that Varp can mediate vesicle tethering/fusion between VAMP7‐positive transporting vesicles and Rab38‐labeled LBs. Consistently, reexpressing Rab38 in FHH ATII cells preferentially recruits VAMP7‐positive vesicles to Rab38‐labeled LBs. Future studies will identify cargo(s) carried by the VAMP7‐positive vesicles, and demonstrate the vesicle tethering/fusion process occurring on LB surface in live ATII cells. Supported by NIH 5T32HL007748 and 5P01HL19737.