A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion

Cargo translocation into dedicated secretory compartments is a crucial aspect of secretion. In conventional secretion, signal peptide-equipped proteins enter the endoplasmic reticulum (ER), while a subset of cargo lacking signal peptides were found to translocate into the ER-Golgi intermediate compartment (ERGIC) in unconventional protein secretion (UcPS). The regulatory events at the ERGIC in UcPS is unclear. Here we reveal the involvement of ERGIC-localized small GTPases, Rab1s (Rab1A and Rab1B), and Rab2A in regulating UcPS cargo transport via TMED10 on the ERGIC. Rab1s enhance TMED10 translocator activity, promoting cargo translocation into the ERGIC, while Rab2A, in collaboration with KIF5B, regulates ERGIC compartmentalization, establishing a UcPS-specific compartment. This investigation highlights the pivotal role of ERGIC-localized Rabs in governing cargo translocation and specifying the ERGIC's function in UcPS.