Okuda Kosaku, Ito Akihiro, Uehara Takashi
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University.
Biol Pharm Bull. 2015;38(9):1434-7. doi: 10.1248/bpb.b15-00364.
Nitric oxide (NO) is a gaseous regulatory factor produced by NO synthases (NOS) and it plays several critical roles via S-nitrosylation of protein cysteine residues. Histone deacetylase (HDAC) functions in the maintenance/balance of chromatin acetylation and contributes to transcriptional supression. It has been reported that S-nitrosylation of HDAC2 is involved in the regulation of deacetylase activity. However, it remains unknown whether other subtypes of the HDAC family are S-nitrosylated. In the present study, we found that HDAC6 is a target of NO. A biotin-switch assay revealed that endogenous HDAC6 is S-nitrosylated by both NO donors and NO derived from the inducible type of NOS in cells treated with cytokines. NO led to suppressed deacetylase activity in vitro and increased acetylated α-tubulin, a major substrate for HDAC6, in A549 cells. These findings suggest that S-nitrosylation of HDAC6 plays a pivotal role in the regulation of protein acetylation.
一氧化氮（NO）是由一氧化氮合酶（NOS）产生的一种气态调节因子，它通过蛋白质半胱氨酸残基的S-亚硝基化发挥多种关键作用。组蛋白脱乙酰酶（HDAC）在染色质乙酰化的维持/平衡中起作用，并有助于转录抑制。据报道，HDAC2的S-亚硝基化参与了脱乙酰酶活性的调节。然而，HDAC家族的其他亚型是否被S-亚硝基化仍不清楚。在本研究中，我们发现HDAC6是NO的一个靶点。生物素转换试验表明，在用细胞因子处理的细胞中，内源性HDAC6被NO供体和诱导型NOS产生的NO进行S-亚硝基化。在A549细胞中，NO导致体外脱乙酰酶活性受到抑制，并增加了HDAC6的主要底物乙酰化α-微管蛋白。这些发现表明，HDAC6的S-亚硝基化在蛋白质乙酰化的调节中起关键作用。
