title: Interaction of SQSTM1 with the motor protein dynein--SQSTM1 is required for normal dynein function and trafficking.
abstract: The dynein motor protein complex is required for retrograde transport of vesicular cargo and for transport of aggregated proteins along microtubules for processing and degradation at perinuclear aggresomes. Disruption of this process leads to dysfunctional endosome accumulation and increased protein aggregation in the cell cytoplasm, both pathological features of neurodegenerative diseases. However, the exact mechanism of dynein functionality in these pathways is still being elucidated. Here, we show that the scaffolding protein SQSTM1 directly interacts with dynein through a previously unidentified dynein-binding site. This interaction is independent of HDAC6, a known interacting protein of both SQSTM1 and dynein. However, knockdown of HDAC6 increases the interaction of SQSTM1 with dynein, indicating a possible competitive interaction. Using different dynein cargoes, we show that SQSTM1 is required for proper dynein motility and trafficking along microtubules. Based on our results, we propose a new model of competitive interaction between SQSTM1 and HDAC6 with dynein. In this model, SQSTM1 would not only affect the association of polyubiquitylated protein aggregates and endosomes with dynein, but would also be required for normal dynein function.
authors.affiliation: Department of Biological Sciences, 331 Funchess Hall, Auburn University, Auburn, AL 36849, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Calderilla-Barbosa
authors.affiliation: Department of Biological Sciences, 331 Funchess Hall, Auburn University, Auburn, AL 36849, USA.
authors.forename: M Lamar
authors.initials: ML
authors.lastname: Seibenhener
authors.affiliation: Department of Biological Sciences, 331 Funchess Hall, Auburn University, Auburn, AL 36849, USA.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Du
authors.affiliation: 10901 North Torrey Pines Road, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Maria-Theresa
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: 10901 North Torrey Pines Road, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.affiliation: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Biological Sciences, 331 Funchess Hall, Auburn University, Auburn, AL 36849, USA.
authors.forename: Marie W
authors.initials: MW
authors.lastname: Wooten
authors.affiliation: Department of Biological Sciences, 331 Funchess Hall, Auburn University, Auburn, AL 36849, USA wootemc@auburn.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wooten
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D056445:Cytoplasmic Dyneins / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000596072:DYNC1I1 protein, human; D006360:Heat-Shock Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C486041:Dync1li1 protein, mouse; D056445:Cytoplasmic Dyneins; C548808:DYNC1LI2 protein, human; C000598724:DYNC1LI2 protein, mouse
keywords: Aggresome; Dynein intermediate chain; HDAC6; Histone deacetylase 6; Late endosome; SQSTM1