Impaired organelle turnover in the FAM134B-mediated neuropathy

遗传性感觉和自主神经病变(HSAN)是以严重感觉丧失和自主神经功能障碍为特征的神经退行性疾病。受影响的人会出现溃疡和受伤，因为他们缺乏急性疼痛反应，而这种反应会提醒身体潜在的组织损伤。我们证明了FAM134B基因的功能缺失突变会导致人类患上一种严重的HSAN。随后，我们确定FAM134B是第一个ER特异性自噬受体，它通过选择性自噬(ER-phagy)促进内质网(ER)的降解。这一效应是通过FAM134B与LC3和GABARAPL2的特异性相互作用而介导的，这两种小的泛素样自噬修饰剂对于靶向和吞噬货物以随后的溶酶体降解至关重要。一贯地，在小鼠中破坏Fam134b会导致内质网扩张，抑制内质网周转，并导致感觉神经元退化。因此，通过FAM134蛋白选择性地吞噬ER对于维持哺乳动物细胞的动态平衡和控制ER的形态和周转是必不可少的。这项延期提案将解决FAM134B介导的细胞器周转的时间和定位以及改变的ER吞噬的下游影响。我们还将研究小鼠中同源的Fam134a和Fam134c基因中断的表型后果以及这些基因在细胞器周转中的作用。

Hereditary sensory and autonomic neuropathies (HSAN) are neurodegenerative disorders characterized by severe sensory loss and autonomic dysfunction. Affected individuals suffer from ulcerations and injuries because they lack an acute pain response which alerts the body of potential tissue damage. We demonstrated that loss-of-function mutations in the previously uncharacterized FAM134B gene lead to a severe form of HSAN in humans. Subsequently, we identified FAM134B as the first ER-specific autophagy receptor which facilitates endoplasmic reticulum (ER) degradation by selective autophagy (ER-phagy). This effect is mediated by the specific interaction of FAM134B with LC3 and GABARAPL2, small ubiquitin-like autophagy modifiers that are critical for both targeting and engulfing cargoes for subsequent lysosomal degradation. Consistently, disruption of Fam134b in mice results in expansions of the ER, inhibition of ER turnover, and degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover. This extension proposal will address the timing and localization of FAM134B-mediated organelle turnover and the downstream effects of altered ER-phagy. We will also investigate the phenotypic consequences of the disruption of the homologous Fam134a and Fam134c genes in mice as well the role of these genes in organelle turnover.