PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation

Author:

Amick Joseph123,Tharkeshwar Arun Kumar123ORCID,Talaia Gabriel123ORCID,Ferguson Shawn M.123ORCID

Affiliation:

1. Department of Cell Biology, Yale University School of Medicine, New Haven, CT

2. Department of Neuroscience, Yale University School of Medicine, New Haven, CT

3. Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT

Abstract

The C9orf72 protein is required for normal lysosome function. In support of such functions, C9orf72 forms a heterotrimeric complex with SMCR8 and WDR41 that is recruited to lysosomes when amino acids are scarce. These properties raise questions about the identity of the lysosomal binding partner of the C9orf72 complex and the amino acid–sensing mechanism that regulates C9orf72 complex abundance on lysosomes. We now demonstrate that an interaction with the lysosomal cationic amino acid transporter PQLC2 mediates C9orf72 complex recruitment to lysosomes. This is achieved through an interaction between PQLC2 and WDR41. The interaction between PQLC2 and the C9orf72 complex is negatively regulated by arginine, lysine, and histidine, the amino acids that PQLC2 transports across the membrane of lysosomes. These results define a new role for PQLC2 in the regulated recruitment of the C9orf72 complex to lysosomes and reveal a novel mechanism that allows cells to sense and respond to changes in the availability of cationic amino acids within lysosomes.

Funder

National Institutes of Health

Publisher

Rockefeller University Press

Subject

Cell Biology

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