Palmitoylation of caspase-6 by HIP14 regulates its activation
Palmitoylation of caspase-6 by HIP14 regulates its activation
复制标题
HIP14对caspase-6棕榈酰化的调节作用
DOI：
10.1038/cdd.2016.139
复制
发表时间：
2016-12
影响因子：
12.4
通讯作者：
Niels H. Skotte;Shaun S. Sanders;R. Singaraja;Dagmar E. Ehrnhoefer;Kuljeet S. Vaid;X. Qiu;Srinivasaragavan Kannan
中科院分区：
文献类型：
--
作者：
Niels H. Skotte;Shaun S. Sanders;R. Singaraja;Dagmar E. Ehrnhoefer;Kuljeet S. Vaid;X. Qiu;Srinivasaragavan Kannan
Caspase-6 (CASP6) 在神经元凋亡过程中的轴突变性以及神经退行性疾病阿尔茨海默病和亨廷顿病中发挥重要作用。降低 CASP6 活性可能有助于恢复这些疾病以及其他疾病（如中风和缺血）中的神经元功能，这些疾病与 CASP6 活性增加有关。寻找降低 CASP6 活性的方法的关键是更深入地了解调节 CASP6 激活的机制。我们发现 CASP6 在翻译后被棕榈酰酰基转移酶 HIP14 棕榈酰化，并且 CASP6 的棕榈酰化抑制其激活。 CASP6 的棕榈酰化在 Hip14−/− 小鼠（HIP14 缺失）和 YAC128 小鼠（亨廷顿病模型）中均减少，其中 HIP14 功能失调而 CASP6 活性增加。分子模型表明，CASP6 的棕榈酰化可能通过底物结合沟的空间阻断和 CASP6 二聚化的抑制来抑制其激活，这两者对于 CASP6 功能都是必需的。我们的研究将棕榈酰化确定为一种新型 CASP6 修饰，并且是 CASP6 活性的关键调节因子。
Caspase-6 (CASP6) has an important role in axonal degeneration during neuronal apoptosis and in the neurodegenerative diseases Alzheimer and Huntington disease. Decreasing CASP6 activity may help to restore neuronal function in these and other diseases such as stroke and ischemia, where increased CASP6 activity has been implicated. The key to finding approaches to decrease CASP6 activity is a deeper understanding of the mechanisms regulating CASP6 activation. We show that CASP6 is posttranslationally palmitoylated by the palmitoyl acyltransferase HIP14 and that the palmitoylation of CASP6 inhibits its activation. Palmitoylation of CASP6 is decreased both in Hip14−/− mice, where HIP14 is absent, and in YAC128 mice, a model of Huntington disease, where HIP14 is dysfunctional and where CASP6 activity is increased. Molecular modeling suggests that palmitoylation of CASP6 may inhibit its activation via steric blockage of the substrate-binding groove and inhibition of CASP6 dimerization, both essential for CASP6 function. Our studies identify palmitoylation as a novel CASP6 modification and as a key regulator of CASP6 activity.