p97/VCP Promotes the Recycling of Endocytic Cargo

Abstract

The endocytic pathway is of central importance for eukaryotic cells, as it enables uptake of extracellular materials, membrane protein quality control and recycling, as well as modulation of receptor signaling. While the ATPase p97 (VCP, Cdc48) has been found to be involved in the fusion of early endosomes and endolysosomal degradation, its role in endocytic trafficking is still incompletely characterized. Here, we identify myoferlin (MYOF), a ferlin family member with functions in membrane trafficking and repair, as a hitherto unknown p97 interactor. The interaction of MYOF with p97 depends on the cofactor PLAA previously linked to endosomal sorting. Besides PLAA, shared interactors of p97 and MYOF comprise several proteins involved in endosomal recycling pathways, including Rab11, Rab14, and the transferrin receptor CD71. Accordingly, a fraction of p97 and PLAA localizes to MYOF-, Rab11-, and Rab14-positive endosomal compartments. Pharmacological inhibition of p97 delays transferrin recycling, indicating that p97 promotes not only the lysosomal degradation, but also the recycling of endocytic cargo.

Abstract

• The ATPase p97/VCP has been linked to endosomal trafficking in the past, but the full range of its involvement in endosomal processes is still unknown.

• The authors used crosslinking-assisted mass spectrometry to identify MYOF as novel p97 binding partner.

• Using immunofluorescence microscopy, they found that a subpopulation of p97 and MYOF localizes to recycling endosomes and that chemical inhibition of p97 delays the recycling of transferrin to the plasma membrane.

• These findings suggest that p97 possesses functions beyond the endolysosomal degradation of endocytic cargo and implicate p97 in MYOF-dependent membrane trafficking and repair pathways.