Critical role of the HDAC6-cortactin axis in human megakaryocytes maturation leading to a proplatelet-formation defect

Kahia Messaoudi; Ashfaq  Ali; Rameez  Ishaq; Alberta  Palazzo; Dominika  Sliwa; Olivier  Bluteau; Sylvie  Souquère; Delphine  Muller; Khadija M.   Diop; Philippe  Rameau; Valérie  Lapierre; Jean-Pierre  Marolleau; Patrick  Matthias; Isabelle  Godin; Gérard  Pierron; Steven Thomas; Steve Watson; Nathalie  Droin; William  Vainchenker; Isabelle  Plo; Hana  Raslova; Najet Debili

doi:10.1038/s41467-017-01690-2

Critical role of the HDAC6-cortactin axis in human megakaryocytes maturation leading to a proplatelet-formation defect

Kahia Messaoudi, Ashfaq Ali, Rameez Ishaq, Alberta Palazzo, Dominika Sliwa, Olivier Bluteau, Sylvie Souquère, Delphine Muller, Khadija M. Diop, Philippe Rameau, Valérie Lapierre, Jean-Pierre Marolleau, Patrick Matthias, Isabelle Godin, Gérard Pierron, Steven Thomas, Steve Watson, Nathalie Droin, William Vainchenker, Isabelle PloHana Raslova , Najet Debili

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

254 Downloads (Pure)

Abstract

Thrombocytopenia is a major side-effect of a new class of anticancer agent that targets histone deacetylase (HDAC). Their mechanism is poorly understood. Here we show that HDAC6 inhibition and genetic knockdown (KD) lead to a strong decrease in human-proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human-MK phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MK, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.

Original language	English
Article number	1786
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/s41467-017-01690-2
Publication status	Published - 27 Nov 2017

Keywords

acetylation
cytoskeleton
platelets

Access to Document

10.1038/s41467-017-01690-2Licence: Creative Commons: Attribution (CC BY)

Messaoudi_et_al_Critical_role_of_the_HDAC6-cortactin_Nature_Communications_2017
Article published in Nature Communications on 27/11/2017 doi:10.1038/s41467-017-01690-2
Final published version, 5.74 MBLicence: Creative Commons: Attribution (CC BY)

https://www.nature.com/articles/s41467-017-01690-2Licence: Creative Commons: Attribution (CC BY)

Cite this

Messaoudi, K., Ali, A., Ishaq, R., Palazzo, A., Sliwa, D., Bluteau, O., Souquère, S., Muller, D., Diop, K. M., Rameau, P., Lapierre, V., Marolleau, J-P., Matthias, P., Godin, I., Pierron, G., Thomas, S., Watson, S., Droin, N., Vainchenker, W., ... Debili, N. (2017). Critical role of the HDAC6-cortactin axis in human megakaryocytes maturation leading to a proplatelet-formation defect. Nature Communications, 8, Article 1786. https://doi.org/10.1038/s41467-017-01690-2

@article{47a0032ce4974c25955057480db84b6e,

title = "Critical role of the HDAC6-cortactin axis in human megakaryocytes maturation leading to a proplatelet-formation defect",

abstract = "Thrombocytopenia is a major side-effect of a new class of anticancer agent that targets histone deacetylase (HDAC). Their mechanism is poorly understood. Here we show that HDAC6 inhibition and genetic knockdown (KD) lead to a strong decrease in human-proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human-MK phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MK, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.",

keywords = "acetylation , cytoskeleton , platelets",

author = "Kahia Messaoudi and Ashfaq Ali and Rameez Ishaq and Alberta Palazzo and Dominika Sliwa and Olivier Bluteau and Sylvie Souqu{\`e}re and Delphine Muller and Diop, {Khadija M.} and Philippe Rameau and Val{\'e}rie Lapierre and Jean-Pierre Marolleau and Patrick Matthias and Isabelle Godin and G{\'e}rard Pierron and Steven Thomas and Steve Watson and Nathalie Droin and William Vainchenker and Isabelle Plo and Hana Raslova and Najet Debili",

year = "2017",

month = nov,

day = "27",

doi = "10.1038/s41467-017-01690-2",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer",

}

Messaoudi, K, Ali, A, Ishaq, R, Palazzo, A, Sliwa, D, Bluteau, O, Souquère, S, Muller, D, Diop, KM, Rameau, P, Lapierre, V, Marolleau, J-P, Matthias, P, Godin, I, Pierron, G, Thomas, S , Watson, S, Droin, N, Vainchenker, W, Plo, I, Raslova , H & Debili, N 2017, 'Critical role of the HDAC6-cortactin axis in human megakaryocytes maturation leading to a proplatelet-formation defect', Nature Communications, vol. 8, 1786. https://doi.org/10.1038/s41467-017-01690-2

TY - JOUR

T1 - Critical role of the HDAC6-cortactin axis in human megakaryocytes maturation leading to a proplatelet-formation defect

AU - Messaoudi, Kahia

AU - Ali, Ashfaq

AU - Ishaq, Rameez

AU - Palazzo, Alberta

AU - Sliwa, Dominika

AU - Bluteau, Olivier

AU - Souquère, Sylvie

AU - Muller, Delphine

AU - Diop, Khadija M.

AU - Rameau, Philippe

AU - Lapierre, Valérie

AU - Marolleau, Jean-Pierre

AU - Matthias, Patrick

AU - Godin, Isabelle

AU - Pierron, Gérard

AU - Thomas, Steven

AU - Watson, Steve

AU - Droin, Nathalie

AU - Vainchenker, William

AU - Plo, Isabelle

AU - Raslova , Hana

AU - Debili, Najet

PY - 2017/11/27

Y1 - 2017/11/27

N2 - Thrombocytopenia is a major side-effect of a new class of anticancer agent that targets histone deacetylase (HDAC). Their mechanism is poorly understood. Here we show that HDAC6 inhibition and genetic knockdown (KD) lead to a strong decrease in human-proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human-MK phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MK, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.

AB - Thrombocytopenia is a major side-effect of a new class of anticancer agent that targets histone deacetylase (HDAC). Their mechanism is poorly understood. Here we show that HDAC6 inhibition and genetic knockdown (KD) lead to a strong decrease in human-proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human-MK phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MK, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.

KW - acetylation

KW - cytoskeleton

KW - platelets

U2 - 10.1038/s41467-017-01690-2

DO - 10.1038/s41467-017-01690-2

M3 - Article

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 1786

ER -

Critical role of the HDAC6-cortactin axis in human megakaryocytes maturation leading to a proplatelet-formation defect

Abstract

Keywords

Access to Document

Fingerprint

Cite this