AKIR-1 regulates proteasome subcellular function in Caenorhabditis elegans
Johanna Pispa,
Elisa Mikkonen,
Leena Arpalahti,
Congyu Jin,
Carmen Martínez-Fernández,
Julián Cerón,
Carina I. Holmberg
Affiliations
Johanna Pispa
Department of Biochemistry and Developmental Biology, Medicum, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
Elisa Mikkonen
Department of Biochemistry and Developmental Biology, Medicum, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
Leena Arpalahti
Department of Biochemistry and Developmental Biology, Medicum, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
Congyu Jin
Department of Anatomy, Medicum, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
Carmen Martínez-Fernández
Modeling Human Diseases in C. elegans Group, Genes, Diseases, and Therapies Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain
Julián Cerón
Modeling Human Diseases in C. elegans Group, Genes, Diseases, and Therapies Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain
Carina I. Holmberg
Department of Biochemistry and Developmental Biology, Medicum, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; Corresponding author
Summary: Polyubiquitinated proteins are primarily degraded by the ubiquitin-proteasome system (UPS). Proteasomes are present both in the cytoplasm and nucleus. Here, we investigated mechanisms coordinating proteasome subcellular localization and activity in a multicellular organism. We identified the nuclear protein-encoding gene akir-1 as a proteasome regulator in a genome-wide Caenorhabditis elegans RNAi screen. We demonstrate that depletion of akir-1 causes nuclear accumulation of endogenous polyubiquitinated proteins in intestinal cells, concomitant with slower in vivo proteasomal degradation in this subcellular compartment. Remarkably, akir-1 is essential for nuclear localization of proteasomes both in oocytes and intestinal cells but affects differentially the subcellular distribution of polyubiquitinated proteins. We further reveal that importin ima-3 genetically interacts with akir-1 and influences nuclear localization of a polyubiquitin-binding reporter. Our study shows that the conserved AKIR-1 is an important regulator of the subcellular function of proteasomes in a multicellular organism, suggesting a role for AKIR-1 in proteostasis maintenance.
