Palmitoylation of caspase-6 by HIP14 regulates its activation

Abstract

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.

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics

“…Caspase-6 (CASP6), another important player in apoptosis, has also been shown to be S-acylated, in this case by zDHHC17 (Skotte et al 2017). Reduced CASP6 S-acylation resulted in increased CASP6 activity, and vice versa (Skotte et al 2017).…”

“…Caspase-6 (CASP6), another important player in apoptosis, has also been shown to be S-acylated, in this case by zDHHC17 (Skotte et al 2017). Reduced CASP6 S-acylation resulted in increased CASP6 activity, and vice versa (Skotte et al 2017). Importantly, CASP6 was shown to play a critical role in neurodegenerative diseases such as Alzheimer disease (AD) and Huntington disease (HD) (Graham et al 2011) and zDHHC17 is known to also play a direct role in HD by mediating the S-acylation of huntingtin (Singaraja et al 2002;Huang et al 2004).…”

Acute regulation of habituation learning via posttranslational palmitoylation

“…Hip14 was originally identified in the context of its interaction with the Huntington's disease-associated Huntingtin protein 42 . Since its discovery, hundreds of potential Hip14 palmitoylation substrates and interacting partners have been identified 34,35,[43][44][45][46][47][48][49][50] .…”

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

“…HIP14 knockout leads to increased apoptosis, whereas HIP14 overexpression results in decreased apoptosis due to reduced NF-κB activation (12). Another study indicated that caspase 6, which plays an important role in apoptosis, can be inhibited by the palmitoyl transferase activity of HIP14 in the mouse brain (93). However, further investigation is needed to clarify whether this effect also occurs in pancreatic beta-cells.…”