Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage
Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage
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DOI：
10.1073/pnas.1821844116
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发表时间：
2019-04-16
影响因子：
11.1
通讯作者：
Petit, Christine
中科院分区：
文献类型：
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作者：
Defourny, Jean;Aghaie, Alain;Petit, Christine
过度接触噪音会引起氧化应激，导致听觉毛细胞受损。适应性过氧化物酶体增殖涉及pejvakin，一种来自气皮蛋白家族的过氧化物酶体相关蛋白，已被证明可以防止这种有害的氧化应激。然而，pejvakin在过氧化物酶体动力学和体内平衡中的作用尚不清楚。在这里，我们发现声音过度刺激诱导野生型小鼠听觉毛细胞中过氧化物酶体的早期和快速选择性自噬降解（噬噬），而不是pejvk（-/-）缺失小鼠。在野生型小鼠中，噪音过度暴露会触发自噬体相关蛋白MAP1LC3B （LC3B；微管相关蛋白1轻链3 β）向过氧化物酶体募集，但Pjvk（-/-）小鼠则不会。我们还发现，pejvakin- lc3b结合涉及到pejvakin的预测伴侣结构域中的lc3相互作用区域。在转染细胞和体内转导的听觉毛细胞中，半胱氨酸诱变实验表明，活性氧诱导的pejvakin- lc3b相互作用和噬噬需要C328和C343这两个最靠近pejvakin C端的半胱氨酸残基。Pjvk和Lc3b cDNA在Pjvk（-/-）小鼠听觉毛细胞中的病毒转导完全恢复了声音诱导的噬噬，完全阻止了氧化应激的发展，并导致正常水平的过氧化物酶体增殖，而Pjvk cDNA仅部分纠正了缺陷。总之，我们的研究结果表明，噬噬在噪声诱导的过氧化物酶体增殖中起着关键作用，并确定噬噬缺陷是噪声性听力损失的一个原因。他们认为，pejvakin作为一种氧化还原激活的噬皮受体/适配器，从而确定了gasdermin家族蛋白以前未知的功能。
Noise overexposure causes oxidative stress, leading to auditory hair cell damage. Adaptive peroxisome proliferation involving pejvakin, a peroxisome-associated protein from the gasdermin family, has been shown to protect against this harmful oxidative stress. However, the role of pejvakin in peroxisome dynamics and homeostasis remains unclear. Here we show that sound overstimulation induces an early and rapid selective autophagic degradation of peroxisomes (pexophagy) in auditory hair cells from wild-type, but not pejvakin-deficient (Pjvk(-/-)), mice. Noise overexposure triggers recruitment of the autophagosome-associated protein MAP1LC3B (LC3B; microtubule-associated protein 1 light chain 3 beta) to peroxisomes in wild-type, but not Pjvk(-/-), mice. We also show that pejvakin-LC3B binding involves an LC3-interacting region within the predicted chaperone domain of pejvakin. In transfected cells and in vivo transduced auditory hair cells, cysteine mutagenesis experiments demonstrated the requirement for both C328 and C343, the two cysteine residues closest to the C terminus of pejvakin, for reactive oxygen species-induced pejvakin-LC3B interaction and pexophagy. The viral transduction of auditory hair cells from Pjvk(-/-) mice in vivo with both Pjvk and Lc3b cDNAs completely restored sound-induced pexophagy, fully prevented the development of oxidative stress, and resulted in normal levels of peroxisome proliferation, whereas Pjvk cDNA alone yielded only a partial correction of the defects. Overall, our results demonstrate that pexophagy plays a key role in noise-induced peroxisome proliferation and identify defective pexophagy as a cause of noise-induced hearing loss. They suggest that pejvakin acts as a redox-activated pexophagy receptor/adaptor, thereby identifying a previously unknown function of gasdermin family proteins.