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The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

ABSTRACT: We recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1's canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.

ORGANISM(S): Homo sapiens

PROVIDER: GSE219209 | GEO | 2023/01/18

REPOSITORIES: GEO

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The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

Project description:The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

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The HAPSTR2 retrogene buffers stress signaling and resilience in mammals.

Project description:We recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1's canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.

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The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

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HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

Project description:HUWE1 is a large, enigmatic HECT domain ubiquitin ligase implicated in the degradation of numerous substrates and regulating diverse pathways including DNA repair, apoptosis, and differentiation. However, the mechanism by which HUWE1 acts in a pleiotropic manner to regulate a myriad of substrates is unknown. Recent work has established a physical and genetic interaction between HUWE1 and C16orf72/HAPSTR1, suggesting that HAPSTR1 positively regulates HUWE1 function. Here, we show that HAPSTR1 is both a HUWE1 substrate, and is required to localize HUWE1 to the nucleus. Quantitative proteomics across diverse cell types reveals that HUWE1 substrates are largely context specific. Transcriptomics following HUWE1 or HAPSTR1 loss of function reveals a broad transcriptional stress response. We show that nuclear HUWE1 impacts stress signaling pathways, including p53 and NFkB-mediated signaling, and is required for cell proliferation. Together, these data define a critical role for nuclear HUWE1 function that is dependent on HAPSTR1.

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HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

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Project description:Mammals have evolved sex-specific adaptations to reduce energy usage in times of food scarcity. These adaptations are well described for peripheral tissue, though much less is known about how the energy-expensive brain adapts to food restriction, and how such adaptations differ across the sexes. Here, we examined how food restriction impacts energy usage and function in the primary visual cortex (V1) of adult male and female mice. Molecular analysis and RNA sequencing revealed that food restriction modulated canonical, energy-regulating pathways including oxidative phosphorylation, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling, significantly in males but not in females V1. Moreover, we found that in contrast to males, food restriction in females non-significantly affected V1 ATP usage and visual coding precision (assessed by orientation selectivity). Decreased serum leptin is necessary for triggering energy-saving changes in male mouse V1 during food restriction. Consistent with this result, we found a significant decrease of serum leptin in food-restricted males but no significant change in food-restricted females. Collectively, our findings demonstrate that cortical function and energy usage in female mice are more resilient to food restriction than in males. The neocortex, therefore, contributes to sex-specific, energy-saving adaptations in response to metabolic challenge.

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C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways

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