Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound

Dagmar E. Ehrnhoefer; Niels H. Skotte; Jeanette Reinshagen; Xiaofan Qiu; Bjorn Windshuegel; Priyadarshini Jaishankar; Safia Ladha; Olga Petina; Mehdi Khankischpur; Yen T. N. Nguyen; Nicholas S. Caron; Adelia Razeto; Matthias Meyer Zu Rheda; Yu Deng; Khuong T. Huynh; Ilka Wittig; Philip Gribbon; Adam R. Renslo; Detlef Geffken; Sheraz Gul; Michael R. Hayden

doi:10.1016/j.chembiol.2019.07.001

Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound

Dagmar E. Ehrnhoefer, Niels H. Skotte, Jeanette Reinshagen, Xiaofan Qiu, Bjorn Windshuegel, Priyadarshini Jaishankar, Safia Ladha, Olga Petina, Mehdi Khankischpur, Yen T. N. Nguyen, Nicholas S. Caron, Adelia Razeto, Matthias Meyer Zu Rheda, Yu Deng, Khuong T. Huynh, Ilka Wittig, Philip Gribbon, Adam R. Renslo, Detlef Geffken, Sheraz GulMichael R. Hayden

2 Citations (Scopus)

Abstract

Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonstrated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mHTT_1-586 fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mHTT_1-586. Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT_1-586 with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis.

Original language	English
Journal	Cell Chemical Biology
Volume	26
Issue number	9
Pages (from-to)	1295-1305.e6
ISSN	2451-9448
DOIs	https://doi.org/10.1016/j.chembiol.2019.07.001
Publication status	Published - 19 Sept 2019
Externally published	Yes

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Ehrnhoefer, D. E., Skotte, N. H., Reinshagen, J., Qiu, X., Windshuegel, B., Jaishankar, P., Ladha, S., Petina, O., Khankischpur, M., Nguyen, Y. T. N., Caron, N. S., Razeto, A., Zu Rheda, M. M., Deng, Y., Huynh, K. T., Wittig, I., Gribbon, P., Renslo, A. R., Geffken, D., ... Hayden, M. R. (2019). Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound. Cell Chemical Biology, 26(9), 1295-1305.e6. https://doi.org/10.1016/j.chembiol.2019.07.001

Ehrnhoefer, DE, Skotte, NH, Reinshagen, J, Qiu, X, Windshuegel, B, Jaishankar, P, Ladha, S, Petina, O, Khankischpur, M, Nguyen, YTN, Caron, NS, Razeto, A, Zu Rheda, MM, Deng, Y, Huynh, KT, Wittig, I, Gribbon, P, Renslo, AR, Geffken, D, Gul, S & Hayden, MR 2019, 'Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound', Cell Chemical Biology, vol. 26, no. 9, pp. 1295-1305.e6. https://doi.org/10.1016/j.chembiol.2019.07.001

@article{a4e25ded70464f67ac498e1e7826b42d,

title = "Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound",

abstract = "Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonstrated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mHTT1-586 fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mHTT1-586. Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT1-586 with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis.",

author = "Ehrnhoefer, {Dagmar E.} and Skotte, {Niels H.} and Jeanette Reinshagen and Xiaofan Qiu and Bjorn Windshuegel and Priyadarshini Jaishankar and Safia Ladha and Olga Petina and Mehdi Khankischpur and Nguyen, {Yen T. N.} and Caron, {Nicholas S.} and Adelia Razeto and {Zu Rheda}, {Matthias Meyer} and Yu Deng and Huynh, {Khuong T.} and Ilka Wittig and Philip Gribbon and Renslo, {Adam R.} and Detlef Geffken and Sheraz Gul and Hayden, {Michael R.}",

year = "2019",

month = sep,

day = "19",

doi = "10.1016/j.chembiol.2019.07.001",

language = "English",

volume = "26",

pages = "1295--1305.e6",

journal = "Chemistry and Biology",

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TY - JOUR

T1 - Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound

AU - Ehrnhoefer, Dagmar E.

AU - Skotte, Niels H.

AU - Reinshagen, Jeanette

AU - Qiu, Xiaofan

AU - Windshuegel, Bjorn

AU - Jaishankar, Priyadarshini

AU - Ladha, Safia

AU - Petina, Olga

AU - Khankischpur, Mehdi

AU - Nguyen, Yen T. N.

AU - Caron, Nicholas S.

AU - Razeto, Adelia

AU - Zu Rheda, Matthias Meyer

AU - Deng, Yu

AU - Huynh, Khuong T.

AU - Wittig, Ilka

AU - Gribbon, Philip

AU - Renslo, Adam R.

AU - Geffken, Detlef

AU - Gul, Sheraz

AU - Hayden, Michael R.

PY - 2019/9/19

Y1 - 2019/9/19

N2 - Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonstrated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mHTT1-586 fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mHTT1-586. Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT1-586 with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis.

AB - Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonstrated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mHTT1-586 fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mHTT1-586. Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT1-586 with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis.

U2 - 10.1016/j.chembiol.2019.07.001

DO - 10.1016/j.chembiol.2019.07.001

M3 - Journal article

C2 - 31353319

SN - 2451-9448

VL - 26

SP - 1295-1305.e6

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 9

ER -

Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound

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