Letter to the editor: “KDAC and the regulation of nonnuclear smooth muscle protein acetylation”

to the editor: We were intrigued to read the paper recently published by Li et al. (4) entitled “Histone deacetylase 8 regulates cortactin deacetylation and contraction in smooth muscle tissues.” The posttranslational modification of nonnuclear smooth muscle proteins by acetylation is emerging as an important regulatory mechanism, and our attention was drawn to several aspects of the article.

First, the authors used the pan-HDAC inhibitor XXIV (as indicated by information provided by the commercial source of the compound: http://www.emdmillipore.com/GB/en/product/HDAC-Inhibitor-XXIV%2C-OSU-HDAC-44—Calbiochem,EMD_BIO-382181?CategoryName=00000026000095e400020023&CategoryDomainName=Merck-MerckMillipore#anchor_PDS), yet claimed it to yield information specific to HDAC8. This seemed to be an overinterpretation and ignored the possibility of a contribution from other HDACs. There was not, for example, any data on the effectiveness of the compound after short hairpin RNA-mediated reduction of HDAC8 expression.

Second, for the coimmunolocalization experiments the appropriate controls (e.g., nonimmune IgG precipitations) were not presented, thus denying the reader complete security that the reported interactions were specific.

Third, the experiments reporting changes in cortactin acetylation were performed using an antibody directed against acetylated lysine residues. It is therefore surprising that the authors chose to focus on only the possibility that cortactin lysine acetylation may have changed with their experimental manoeuvers. The antibody, one presumes, will have picked up many proteins whose acetylation status will have been altered.

Fourth, it is disconcerting that the authors failed to place their work in an appropriate context of the topic. Large-scale proteomic studies (e.g., Ref. 5) have revealed several thousand proteins, many resident outwith the nucleus and related to filamentous protein frameworks, to be targets for acetylation, yet this broad landscape was not mentioned. In addition, not all, of course, but many aspects of the study by Li et al. (4) with respect to the potential role that HDAC8 may have in mediating nonnuclear, cytoskeletal protein acetylation and, thereby, smooth muscle force production were similar to work reported previously in vascular and nonvascular smooth muscle (1, 2, 3). Yet Li et al. (4) made no reference to these papers. In this context we (1) previously reported 1) the smooth muscle relaxatory actions of the HDAC8 inhibitor compound 2 and the pan-HDAC inhibitor trichostatin A; 2) the coimmunoprecipitation of HDAC8 with several smooth muscle filamentous proteins including cortactin; and 3) the increased immunoprecipitation of acetylated forms of several smooth muscle filamentous proteins, including cortactin, following HDAC8 inhibition. Indeed, in appreciation of the burgeoning data suggestive of many nonnuclear proteins being targets of acetylation, in smooth muscle and other tissues, we referred to deacetylases as KDACs (for lysine deacetylase) rather than HDACs (1). This seems particularly pertinent for KDAC8.

In summary, we welcome the contributions of Li et al. (4) to the topic of smooth muscle protein modification by KDACs, yet suggest it should not go unnoticed that much of the merit of this article is to add information to an already existing body of work on this topic.

GRANTS

Our work referred to herein was supported by the British Heart Foundation (PG/09/075) and the Medical Research Council (G00800202 and MR/L009560/1).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

M.J.T., M.K.B., and G.N.E.F. approved final version of the manuscript.