Huntingtin inhibits caspase-3 activation

Yu Zhang, Blair R. Leavitt, Jeremy M. Van Raamsdonk, Ioannis Dragatsis, Dan Goldowitz, Marcy E. MacDonald, Michael R. Hayden, Robert M. Friedlander

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Huntington's disease results from a mutation in the HD gene encoding for the protein huntingtin. The function of huntingtin, although beginning to be elucidated, remains largely unclear. To probe the prosurvival function of huntingtin, we modulate levels of wild-type huntingtin in a number of cellular and in vivo models. Huntingtin depletion resulted in caspase-3 activation, and overexpression of huntingtin resulted in caspase-3 inhibition. Additionally, we demonstrate that huntingtin physically interacts with active caspase-3. Interestingly, mutant huntingtin binds active caspase-3 with a lower affinity and lower inhibitory effect on active caspase-3 than does wild-type huntingtin. Although reduction of huntingtin levels resulted in caspase-3 activation in all conditions examined, the cellular response was cell-type specific. Depletion of huntingtin resulted in either overt cell death, or in increased vulnerability to cell death. These data demonstrate that huntingtin inhibits caspase-3 activity, suggesting a mechanism whereby caspase-mediated huntingtin depletion results in a detrimental amplification cascade leading to further caspase-3 activation, resulting in cell dysfunction and cell death.

Original languageEnglish (US)
Pages (from-to)5896-5906
Number of pages11
JournalEMBO Journal
Volume25
Issue number24
DOIs
StatePublished - Dec 13 2006

Fingerprint

Caspase 3
Chemical activation
Cell death
Cell Death
Gene encoding
Huntington Disease
Caspases
Amplification
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Zhang, Y., Leavitt, B. R., Van Raamsdonk, J. M., Dragatsis, I., Goldowitz, D., MacDonald, M. E., ... Friedlander, R. M. (2006). Huntingtin inhibits caspase-3 activation. EMBO Journal, 25(24), 5896-5906. https://doi.org/10.1038/sj.emboj.7601445

Huntingtin inhibits caspase-3 activation. / Zhang, Yu; Leavitt, Blair R.; Van Raamsdonk, Jeremy M.; Dragatsis, Ioannis; Goldowitz, Dan; MacDonald, Marcy E.; Hayden, Michael R.; Friedlander, Robert M.

In: EMBO Journal, Vol. 25, No. 24, 13.12.2006, p. 5896-5906.

Research output: Contribution to journalArticle

Zhang, Y, Leavitt, BR, Van Raamsdonk, JM, Dragatsis, I, Goldowitz, D, MacDonald, ME, Hayden, MR & Friedlander, RM 2006, 'Huntingtin inhibits caspase-3 activation', EMBO Journal, vol. 25, no. 24, pp. 5896-5906. https://doi.org/10.1038/sj.emboj.7601445
Zhang Y, Leavitt BR, Van Raamsdonk JM, Dragatsis I, Goldowitz D, MacDonald ME et al. Huntingtin inhibits caspase-3 activation. EMBO Journal. 2006 Dec 13;25(24):5896-5906. https://doi.org/10.1038/sj.emboj.7601445
Zhang, Yu ; Leavitt, Blair R. ; Van Raamsdonk, Jeremy M. ; Dragatsis, Ioannis ; Goldowitz, Dan ; MacDonald, Marcy E. ; Hayden, Michael R. ; Friedlander, Robert M. / Huntingtin inhibits caspase-3 activation. In: EMBO Journal. 2006 ; Vol. 25, No. 24. pp. 5896-5906.
@article{65ca2adb23a04a9caf185421aa01b762,
title = "Huntingtin inhibits caspase-3 activation",
abstract = "Huntington's disease results from a mutation in the HD gene encoding for the protein huntingtin. The function of huntingtin, although beginning to be elucidated, remains largely unclear. To probe the prosurvival function of huntingtin, we modulate levels of wild-type huntingtin in a number of cellular and in vivo models. Huntingtin depletion resulted in caspase-3 activation, and overexpression of huntingtin resulted in caspase-3 inhibition. Additionally, we demonstrate that huntingtin physically interacts with active caspase-3. Interestingly, mutant huntingtin binds active caspase-3 with a lower affinity and lower inhibitory effect on active caspase-3 than does wild-type huntingtin. Although reduction of huntingtin levels resulted in caspase-3 activation in all conditions examined, the cellular response was cell-type specific. Depletion of huntingtin resulted in either overt cell death, or in increased vulnerability to cell death. These data demonstrate that huntingtin inhibits caspase-3 activity, suggesting a mechanism whereby caspase-mediated huntingtin depletion results in a detrimental amplification cascade leading to further caspase-3 activation, resulting in cell dysfunction and cell death.",
author = "Yu Zhang and Leavitt, {Blair R.} and {Van Raamsdonk}, {Jeremy M.} and Ioannis Dragatsis and Dan Goldowitz and MacDonald, {Marcy E.} and Hayden, {Michael R.} and Friedlander, {Robert M.}",
year = "2006",
month = "12",
day = "13",
doi = "10.1038/sj.emboj.7601445",
language = "English (US)",
volume = "25",
pages = "5896--5906",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "24",

}

TY - JOUR

T1 - Huntingtin inhibits caspase-3 activation

AU - Zhang, Yu

AU - Leavitt, Blair R.

AU - Van Raamsdonk, Jeremy M.

AU - Dragatsis, Ioannis

AU - Goldowitz, Dan

AU - MacDonald, Marcy E.

AU - Hayden, Michael R.

AU - Friedlander, Robert M.

PY - 2006/12/13

Y1 - 2006/12/13

N2 - Huntington's disease results from a mutation in the HD gene encoding for the protein huntingtin. The function of huntingtin, although beginning to be elucidated, remains largely unclear. To probe the prosurvival function of huntingtin, we modulate levels of wild-type huntingtin in a number of cellular and in vivo models. Huntingtin depletion resulted in caspase-3 activation, and overexpression of huntingtin resulted in caspase-3 inhibition. Additionally, we demonstrate that huntingtin physically interacts with active caspase-3. Interestingly, mutant huntingtin binds active caspase-3 with a lower affinity and lower inhibitory effect on active caspase-3 than does wild-type huntingtin. Although reduction of huntingtin levels resulted in caspase-3 activation in all conditions examined, the cellular response was cell-type specific. Depletion of huntingtin resulted in either overt cell death, or in increased vulnerability to cell death. These data demonstrate that huntingtin inhibits caspase-3 activity, suggesting a mechanism whereby caspase-mediated huntingtin depletion results in a detrimental amplification cascade leading to further caspase-3 activation, resulting in cell dysfunction and cell death.

AB - Huntington's disease results from a mutation in the HD gene encoding for the protein huntingtin. The function of huntingtin, although beginning to be elucidated, remains largely unclear. To probe the prosurvival function of huntingtin, we modulate levels of wild-type huntingtin in a number of cellular and in vivo models. Huntingtin depletion resulted in caspase-3 activation, and overexpression of huntingtin resulted in caspase-3 inhibition. Additionally, we demonstrate that huntingtin physically interacts with active caspase-3. Interestingly, mutant huntingtin binds active caspase-3 with a lower affinity and lower inhibitory effect on active caspase-3 than does wild-type huntingtin. Although reduction of huntingtin levels resulted in caspase-3 activation in all conditions examined, the cellular response was cell-type specific. Depletion of huntingtin resulted in either overt cell death, or in increased vulnerability to cell death. These data demonstrate that huntingtin inhibits caspase-3 activity, suggesting a mechanism whereby caspase-mediated huntingtin depletion results in a detrimental amplification cascade leading to further caspase-3 activation, resulting in cell dysfunction and cell death.

UR - http://www.scopus.com/inward/record.url?scp=33845720388&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845720388&partnerID=8YFLogxK

U2 - 10.1038/sj.emboj.7601445

DO - 10.1038/sj.emboj.7601445

M3 - Article

VL - 25

SP - 5896

EP - 5906

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 24

ER -