title: Inositol hexakisphosphate kinase 1 (IP6K1) activity is required for cytoplasmic dynein-driven transport.
abstract: Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP7), are conserved eukaryotic signaling molecules that possess pyrophosphate and monophosphate moieties. Generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine pyrophosphorylation. Here, we report inositol pyrophosphates as novel regulators of cytoplasmic dynein-driven vesicle transport. Mammalian cells lacking IP6K1 display defects in dynein-dependent trafficking pathways, including endosomal sorting, vesicle movement, and Golgi maintenance. Expression of catalytically active but not inactive IP6K1 reverses these defects, suggesting a role for inositol pyrophosphates in these processes. Endosomes derived from slime mold lacking inositol pyrophosphates also display reduced dynein-directed microtubule transport. We demonstrate that Ser51 in the dynein intermediate chain (IC) is a target for pyrophosphorylation by IP7, and this modification promotes the interaction of the IC N-terminus with the p150(Glued) subunit of dynactin. IC-p150(Glued) interaction is decreased, and IC recruitment to membranes is reduced in cells lacking IP6K1. Our study provides the first evidence for the involvement of IP6Ks in dynein function and proposes that inositol pyrophosphate-mediated pyrophosphorylation may act as a regulatory signal to enhance dynein-driven transport.
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India Graduate Studies, Manipal University, Manipal, India.
authors.forename: Manasa
authors.initials: M
authors.lastname: Chanduri
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400005, India.
authors.forename: Ashim
authors.initials: A
authors.lastname: Rai
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India Graduate Studies, Manipal University, Manipal, India.
authors.forename: Aushaq Bashir
authors.initials: AB
authors.lastname: Malla
authors.affiliation: Department of Chemistry, Princeton University, Washington Rd, Princeton, NJ 08544, U.S.A.
authors.forename: Mingxuan
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Princeton University, Washington Rd, Princeton, NJ 08544, U.S.A.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Fiedler
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400005, India.
authors.forename: Roop
authors.initials: R
authors.lastname: Mallik
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India.
authors.forename: Rashna
authors.initials: R
authors.lastname: Bhandari
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000378:metabolism*; D004398:Dyneins / Q000378:metabolism*; D011992:Endosomes / Q000201:enzymology; D005260:Female; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D021381:Protein Transport
chemical_list: C485444:Ihpk1 protein, mouse; D007295:Inositol Phosphates; D017856:Phosphotransferases (Phosphate Group Acceptor); C115134:IP6K1 protein, human; D004398:Dyneins
keywords: dynactin; dynein; inositol hexakisphosphate kinase 1; inositol pyrophosphates; protein pyrophosphorylation