ADP ribosylation factor-like GTPase 6-interacting protein 5 (ARL6IP5): a prenylated Rab acceptor protein 1 (PRA1) family protein that shapes the ER membrane and regulates ER-phagy.

The prenylated Rab acceptor protein 1 (PRA1) domain is a conserved domain encompassing four transmembrane domains (TMDs). ARL6IP5 (ADP ribosylation factor-like GTPase 6-interacting protein 5) is a member of the PRA1 family and interacts with the reticulon-homology domain (RHD)-containing proteins including ARL6IP1 (ADP ribosylation factor-like GTPase 6-interacting protein 1) and FAM134B. The RHD is a conserved domain encompassing two short hairpin TMDs and acts as a membrane-shaping unit for endoplasmic reticulum (ER) morphology and ER-phagy. However, the involvement of ARL6IP5 in ER morphology and ER-phagy remains unclear. We recently characterized ARL6IP5 as an ER membrane-shaping protein and found that ARL6IP5 constricts the ER membrane in a manner similar to ARL6IP1, possibly via short hairpin configuration of the TMDs in the PRA1 domain. ARL6IP5 also plays a redundant role with ARL6IP1 in shaping the ER membrane. Importantly, depletion of ARL6IP5 impaired FAM134B-meadited ER-phagy, which is reminiscent of ARL6IP1 depletion. These results suggested that ARL6IP5 acts as an ER membrane-shaping protein that regulates ER-phagy, underscoring the importance of the PRA1 domain. Although ARL6IP5 and ARL6IP1 are confusable protein names and seem to have similar roles in ER-phagy, we clarify in this punctum that they are distinct classes of ER membrane-shaping proteins.