Rab6-mediated retrograde transport regulates inner nuclear membrane targeting of caveolin-2 in response to insulin.

Here, we have identified a retrograde transport pathway of caveolin-2 (cav-2) for its regulatory function in the nucleus. Confocal microscopy analysis, photoactivation experiments and subcellular fractionation revealed that cav-2 localized in the Golgi was transported to the inner nuclear membrane (INM) in response to insulin. Exogenous caveolin-1 (cav-1) and P132L-cav-1 expression did not affect the Golgi localization and insulin-induced INM targeting of cav-2. Cav-2(DKV) mutant in the endoplasmic reticulum (ER) was unable to translocate to the INM in response to insulin. The GTP-bound form of Rab6 promoted, but Rab6 siRNA and the GDP-bound form of Rab6 abrogated, retrograde trafficking of cav-2 from the Golgi to ER. Colchicine or nocodazole treatment abolished insulin-induced INM targeting of cav-2. Knock down of gp210 inhibited insulin-induced import of cav-2 from ER/outer nuclear membrane (ONM) to the INM. The INM-targeted cav-2 prevented heterochromatinization and promoted transcriptional activation of Elk-1 and signal transducer and activator of transcription 3 (STAT3). The results provide molecular mechanisms for insulin-induced INM translocation of cav-2 initiated (i) by Golgi-to-ER retrograde trafficking of cav-2 via microtubule-based Rab6-GTP-dependent transport and subsequently processed (ii) by gp210-mediated import of cav-2 from ER/ONM to INM.