Inositol Hexakisphosphate Kinase 1 (IP6K1) Activity is Required for Cytoplasmic Dynein-driven Transport

Overview

Journal Biochem J

Specialty Biochemistry

Date 2016 Jul 31

PMID 27474409

Citations 37

Authors

Manasa Chanduri

Ashim Rai

Aushaq Bashir Malla

Mingxuan Wu

Dorothea Fiedler

Roop Mallik

Rashna Bhandari

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Bhandari R, Juluri K, Resnick A, Snyder S . Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis. Proc Natl Acad Sci U S A. 2008; 105(7):2349-53. PMC: 2268139. DOI: 10.1073/pnas.0712227105. View

Karki S, Tokito M, Holzbaur E . Casein kinase II binds to and phosphorylates cytoplasmic dynein. J Biol Chem. 1997; 272(9):5887-91. DOI: 10.1074/jbc.272.9.5887. View

Soppina V, Rai A, Ramaiya A, Barak P, Mallik R . Tug-of-war between dissimilar teams of microtubule motors regulates transport and fission of endosomes. Proc Natl Acad Sci U S A. 2009; 106(46):19381-6. PMC: 2770008. DOI: 10.1073/pnas.0906524106. View

Thota S, Unnikannan C, Thampatty S, Manorama R, Bhandari R . Inositol pyrophosphates regulate RNA polymerase I-mediated rRNA transcription in Saccharomyces cerevisiae. Biochem J. 2014; 466(1):105-14. PMC: 4325516. DOI: 10.1042/BJ20140798. View

Pfister K . Distinct functional roles of cytoplasmic dynein defined by the intermediate chain isoforms. Exp Cell Res. 2015; 334(1):54-60. PMC: 4433767. DOI: 10.1016/j.yexcr.2014.12.013. View

Williams F, Fiedler D . A Fluorescent Sensor and Gel Stain for Detection of Pyrophosphorylated Proteins. ACS Chem Biol. 2015; 10(9):1958-63. DOI: 10.1021/acschembio.5b00256. View

Vaughan K, Vallee R . Cytoplasmic dynein binds dynactin through a direct interaction between the intermediate chains and p150Glued. J Cell Biol. 1995; 131(6 Pt 1):1507-16. PMC: 2120689. DOI: 10.1083/jcb.131.6.1507. View

Jadav R, Chanduri M, Sengupta S, Bhandari R . Inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1 is required for homologous recombination repair. J Biol Chem. 2012; 288(5):3312-21. PMC: 3561551. DOI: 10.1074/jbc.M112.396556. View

Rapaport D, Auerbach W, Naslavsky N, Pasmanik-Chor M, Galperin E, Fein A . Recycling to the plasma membrane is delayed in EHD1 knockout mice. Traffic. 2006; 7(1):52-60. DOI: 10.1111/j.1600-0854.2005.00359.x. View

10.

Yates L, Fiedler D . Establishing the stability and reversibility of protein pyrophosphorylation with synthetic peptides. Chembiochem. 2015; 16(3):415-23. DOI: 10.1002/cbic.201402589. View

11.

Saiardi A, Nagata E, Luo H, Snowman A, Snyder S . Identification and characterization of a novel inositol hexakisphosphate kinase. J Biol Chem. 2001; 276(42):39179-85. DOI: 10.1074/jbc.M106842200. View

12.

Shevchenko A, Wilm M, Vorm O, Mann M . Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal Chem. 1996; 68(5):850-8. DOI: 10.1021/ac950914h. View

13.

Wu M, Dul B, Trevisan A, Fiedler D . Synthesis and characterization of non-hydrolysable diphosphoinositol polyphosphate second messengers. Chem Sci. 2013; 4(1):405-410. PMC: 3558982. DOI: 10.1039/C2SC21553E. View

14.

Morgan J, Song Y, Barbar E . Structural dynamics and multiregion interactions in dynein-dynactin recognition. J Biol Chem. 2011; 286(45):39349-59. PMC: 3234759. DOI: 10.1074/jbc.M111.296277. View

15.

Hammer 3rd J, Sellers J . Walking to work: roles for class V myosins as cargo transporters. Nat Rev Mol Cell Biol. 2011; 13(1):13-26. DOI: 10.1038/nrm3248. View

16.

Illies C, Gromada J, Fiume R, Leibiger B, Yu J, Juhl K . Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic beta cells. Science. 2007; 318(5854):1299-302. DOI: 10.1126/science.1146824. View

17.

King S, Brown C, Maier K, Quintyne N, Schroer T . Analysis of the dynein-dynactin interaction in vitro and in vivo. Mol Biol Cell. 2003; 14(12):5089-97. PMC: 284810. DOI: 10.1091/mbc.e03-01-0025. View

18.

Szijgyarto Z, Garedew A, Azevedo C, Saiardi A . Influence of inositol pyrophosphates on cellular energy dynamics. Science. 2011; 334(6057):802-5. DOI: 10.1126/science.1211908. View

19.

Shears S, Gokhale N, Wang H, Zaremba A . Diphosphoinositol polyphosphates: what are the mechanisms?. Adv Enzyme Regul. 2010; 51(1):13-25. PMC: 3507380. DOI: 10.1016/j.advenzreg.2010.09.008. View

20.

Beausoleil S, Villen J, Gerber S, Rush J, Gygi S . A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol. 2006; 24(10):1285-92. DOI: 10.1038/nbt1240. View