title: Histone deacetylase 6-mediated deacetylation of α-tubulin coordinates cytoskeletal and signaling events during platelet activation.
abstract: The tubulin cytoskeleton plays a key role in maintaining the characteristic quiescent discoid shape of resting platelets. Upon activation, platelets undergo a dramatic change in shape; however, little is known of how the microtubule system contributes to regulating platelet shape and function. Here we investigated the role of the covalent modification of α-tubulin by acetylation in the regulation of platelet physiology during activation. Superresolution microscopy analysis of the platelet tubulin cytoskeleton showed that the marginal band together with an interconnected web of finer tubulin structures collapsed upon platelet activation with the glycoprotein VI (GPVI)-agonist collagen-related peptide (CRP). Western blot analysis revealed that α-tubulin was acetylated in resting platelets and deacetylated during platelet activation. Tubacin, a specific inhibitor of the tubulin deacetylase HDAC6, prevented tubulin deacetylation upon platelet activation with CRP. Inhibition of HDAC6 upregulated tubulin acetylation and disrupted the organization of the platelet microtubule marginal band without significantly affecting platelet volume changes in response to CRP stimulation. HDAC6 inhibitors also inhibited platelet aggregation in response to CRP and blocked platelet signaling events upstream of platelet Rho GTPase activation. Together, these findings support a role for acetylation signaling in controlling the resting structure of the platelet tubulin marginal band as well as in the coordination of signaling systems that drive platelet cytoskeletal changes and aggregation.
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon;
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Aslan
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Phillips
authors.forename: Laura D
authors.initials: LD
authors.lastname: Healy
authors.forename: Asako
authors.initials: A
authors.lastname: Itakura
authors.forename: Jiaqing
authors.initials: J
authors.lastname: Pang
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
mesh_terms: D001792:Blood Platelets / Q000166:cytology / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D010455:Peptides; D014404:Tubulin; C435908:collagen-related peptide; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; acetylation; platelets; tubulin
references.citation: J Thromb Haemost. 2007 Mar;5(3):535-41
references.pmid: 17319906
references.citation: Blood. 2008 May 1;111(9):4605-16
references.pmid: 18230754
references.citation: J Mol Cell Cardiol. 2008 Feb;44(2):429-34
references.pmid: 18054038
references.citation: J Thromb Haemost. 2013 Jan;11(1):35-46
references.pmid: 23121917
references.citation: J Clin Invest. 1979 Mar;63(3):443-8
references.pmid: 429563
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4389-94
references.pmid: 12677000
references.citation: Methods Mol Biol. 2012;788:91-100
references.pmid: 22130702
references.citation: Nature. 1969 Feb 8;221(5180):563-5
references.pmid: 5789306
references.citation: Mol Cell Biol. 2002 Sep;22(17):6023-33
references.pmid: 12167697
references.citation: Am J Pathol. 1968 Sep;53(3):447-61
references.pmid: 5697984
references.citation: Blood. 2012 Oct 25;120(17):3594-602
references.pmid: 22936655
references.citation: J Biol Chem. 2005 Nov 25;280(47):39474-84
references.pmid: 16195235
references.citation: Blood. 1997 Apr 1;89(7):2336-46
references.pmid: 9116277
references.citation: Nat Rev Drug Discov. 2003 Oct;2(10):775-89
references.pmid: 14526381
references.citation: Appl Spectrosc. 2011 Sep;65(9):967-80
references.pmid: 21929850
references.citation: J Clin Invest. 2005 Dec;115(12):3355-62
references.pmid: 16322780
references.citation: Nat Rev Mol Cell Biol. 2011 Nov 16;12(12):773-86
references.pmid: 22086369
references.citation: Br J Haematol. 2010 Apr;149(1):124-36
references.pmid: 20148881
references.citation: Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1544-51
references.pmid: 23640496
references.citation: Blood. 2010 Aug 19;116(7):1147-56
references.pmid: 20439620
references.citation: Nat Med. 2002 Nov;8(11):1227-34
references.pmid: 12411949
references.citation: J Thromb Haemost. 2005 Aug;3(8):1752-62
references.pmid: 16102042
references.citation: Oncogene. 2007 Aug 13;26(37):5310-8
references.pmid: 17694074
references.citation: Curr Opin Cell Biol. 2008 Feb;20(1):71-6
references.pmid: 18226514
references.citation: Blood. 1978 Feb;51(2):307-16
references.pmid: 620086
references.citation: Mol Cell. 2003 Feb;11(2):437-44
references.pmid: 12620231
references.citation: Exp Cell Res. 1984 Nov;155(1):198-212
references.pmid: 6386495
references.citation: Am J Physiol Cell Physiol. 2013 Sep;305(5):C519-28
references.pmid: 23784547
references.citation: J Physiol. 1971 Apr;214(1):145-58
references.pmid: 5575351
references.citation: Blood. 2011 Sep 15;118(11):3129-36
references.pmid: 21757621
references.citation: Biol Cell. 2008 Feb;100(2):97-108
references.pmid: 18199048
references.citation: Am J Pathol. 1998 Feb;152(2):597-609
references.pmid: 9466587
references.citation: Blood. 1967 Nov;30(5):625-35
references.pmid: 6073858
references.citation: Trends Cell Biol. 2008 Jun;18(6):291-7
references.pmid: 18472263
references.citation: J Clin Invest. 1980 Aug;66(2):284-91
references.pmid: 6772671
references.citation: Oncogene. 2007 Aug 13;26(37):5468-76
references.pmid: 17694087
references.citation: Nat Cell Biol. 2008 Nov;10(11):1356-64
references.pmid: 18931661
references.citation: Am J Physiol Cell Physiol. 2013 Dec 15;305(12):C1211-3
references.pmid: 24108865
references.citation: EMBO J. 2000 Mar 15;19(6):1176-9
references.pmid: 10716917
references.citation: Cell Mol Bioeng. 2012 Dec;5(4):488-492
references.pmid: 23585817
references.citation: Blood. 2012 Nov 15;120(20):4215-8
references.pmid: 22955928
references.citation: Blood. 2005 Dec 15;106(13):4076-85
references.pmid: 16118321
references.citation: Blood. 1968 May;31(5):604-22
references.pmid: 5646304
references.citation: Exp Hematol. 2012 Jul;40(7):564-74
references.pmid: 22381681
references.citation: J Cell Sci. 2009 Oct 1;122(Pt 19):3531-41
references.pmid: 19737819
references.citation: Curr Biol. 2001 Apr 17;11(8):579-86
references.pmid: 11369202
references.citation: Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2341-9
references.pmid: 21071698