The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease
The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease
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DOI：
10.1089/ars.2019.7724
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发表时间：
2019-06-24
影响因子：
6.6
通讯作者：
Garzon, Javier
中科院分区：
文献类型：
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作者：
Cortes-Montero, Elsa;Rodriguez-Munoz, Maria;Garzon, Javier
目的：组氨酸三联体核苷酸结合蛋白1（HINT 1）具有促凋亡和肿瘤抑制活性。HINT 1与转录因子如teneurin 1和G蛋白信号转导17（RGS）（Z2）蛋白的调节因子结合，该蛋白包含小泛素样修饰物（SUMO），并与几种类型的癌症有关。HINT 1通过RGSZ 2的富含半胱氨酸的结构域和偶联的神经型一氧化氮合酶（nNOS）提供的锌离子与蛋白质如PKC γ和Raf-1相互作用。最近，一系列的HINT 1突变体已被报道导致人类常染色体隐性轴突神经病与神经性肌强直（ARAN-NM）。然而，这些突变体诱导的HINT 1功能的具体改变仍有待阐明。由于类小泛素化修饰蛋白质结合和转录调控，我们研究了HINT 1是否表现出锌和氧化还原调节的类小泛素化酶活性，这可能在这些突变体中发生改变。结果：HINT 1具有半胱氨酸蛋白酶活性，可从多种信号蛋白中去除SUMO。HINT 1类小泛素化酶活性被锌阻断，并通过一氧化氮或钙激活的钙调蛋白（CaM）释放。HINT 1在C末端区域含有SUMO相互作用基序（110-116 HIHLHVL）和催化三联体Cys 84-Asp 87-His 114。因此，可能由RGSZ 2-nNOS复合物提供的锌可能与Cys 84结合以阻断HINT 1异肽酶活性。创新：迄今为止，HINT 1是唯一一种受两种交替途径调节的sumoylase，即氧化还原和钙激活的CaM。结论：15个人类HINT 1突变体报告导致ARAN-NM表现出改变sumoylase活性，这可能有助于这种人类运动疾病的发病。
Aims: Histidine triad nucleotide-binding protein 1 (HINT1) exhibits proapoptotic and tumor-suppressive activity. HINT1 binds to transcription factors such as teneurin1 and to the regulator of G protein signaling 17 (RGS) (Z2) protein, which incorporates the small ubiquitin-like modifier (SUMO), and is implicated in several types of cancer. HINT1 interacts with proteins such as PKC gamma and Raf-1 through zinc ions provided by the cysteine-rich domain of RGSZ2 and the coupled neural nitric oxide synthase (nNOS). Recently, a series of HINT1 mutants have been reported to cause human autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM). However, the specific alteration in the function of HINT1 induced by these mutants remains to be elucidated. Because sumoylation modifies protein association and transcriptional regulation, we investigated whether HINT1 exhibits zinc- and redox-regulated sumoylase activity, which may be altered in those mutants. Results: HINT1 exhibits cysteine protease activity to remove SUMO from a variety of signaling proteins. HINT1 sumoylase activity is blocked by zinc, and it is released by nitric oxide or calcium-activated calmodulin (CaM). HINT1 contains a SUMO-interacting motif (110-116 HIHLHVL) and the catalytic triad Cys84-Asp87-His114 in the C-terminal region. Thus, zinc probably provided by the RGSZ2-nNOS complex may bind to Cys84 to block HINT1 isopeptidase activity. Innovation: To date, HINT1 is the only sumoylase that is regulated by two alternate pathways, redox- and calcium-activated CaM. Conclusion: The 15 human HINT1 mutants reported to cause ARAN-NM exhibited altered sumoylase activity, which may contribute to the onset of this human motor disease.