Huntingtin-Associated Protein 1 in Mouse Hypothalamus Stabilizes Glucocorticoid Receptor in Stress Response.

Xingxing Chen,Ning Xin,Qiong Liu,Xingshun Xu,Louyin Zhu,Weili Yang,Peng Yin,Shihua Li,Yongcheng Pan,Xiao-Jiang Li

doi:10.3389/fncel.2020.00125

Abstract

Huntingtin-associated protein 1 (Hap1) was initially identified as a brain-enriched protein that binds to the Huntington’s disease protein, huntingtin. Unlike huntingtin that is ubiquitously expressed in the brain, Hap1 is enriched in the brain with the highest expression level in the hypothalamus. The selective enrichment of Hap1 in the hypothalamus suggests that Hap1 may play a specific role in hypothalamic function that can regulate metabolism and stress response. Here we report that Hap1 is colocalized and interacts with the glucocorticoid receptor (GR) in mouse hypothalamic neurons. Genetic depletion of Hap1 reduced the expression level of GR in the hypothalamus. Dexamethasone, a GR agonist, treatment or fasting of mice induced stress, resulting in increased expression of Hap1 in the hypothalamus. However, when Hap1 was absent, these treatments promoted GR reduction in the hypothalamus. In cultured cells, loss of Hap1 shortened the half-life of GR. These findings suggest that Hap1 stabilizes GR in the cytoplasm and that Hap1 dysfunction or deficiency may alter animal’s stress response.

Highlights

Huntingtin-associated protein 1 (Hap1) was first identified as an interacting partner of huntingtin (Htt), the protein product of the Huntington’s disease (HD) gene (Li et al, 1995)
To investigate whether Hap1 is associated with glucocorticoid receptor (GR), an important intracellular receptor for stress response, in the hypothalamus, the distribution patterns of Hap1 and GR in hypothalamus were immunohistochemically analyzed
Double-immunofluorescent staining using anti-Hap1 (EM77) and GR antibody in sagittal mouse brain section showed that Hap1 and GR were highly expressed in the hypothalamus, especially in the paraventricular nucleus (PVN), which is the important neuroendocrine nucleus that regulates stress (Benarroch, 2005; Herman et al, 2016; Figures 1A–C)

Summary

Introduction

Huntingtin-associated protein 1 (Hap1) was first identified as an interacting partner of huntingtin (Htt), the protein product of the Huntington’s disease (HD) gene (Li et al, 1995). Both Htt and Hap are found to be involved in intracellular trafficking, and abnormal interaction of mutant Htt with Hap affects the intracellular transport of various important molecules (Gauthier et al, 2004; Twelvetrees et al, 2010; Keryer et al, 2011; Roux et al, 2012; Mackenzie et al, 2014; Wong and Holzbaur, 2014). The function of Hap in the hypothalamus that expresses abundant Hap remains unclear

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