Impaired organelle turnover in the FAM134B-mediated neuropathy

遗传性感觉和自主神经病变（HSAN）是一种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。受影响的个体遭受溃疡和伤害，因为他们缺乏急性疼痛反应，提醒身体潜在的组织损伤。我们证明了以前未表征的FAM134B基因的功能丧失突变导致人类严重形式的HSAN。随后，我们发现FAM134B是第一个内质网特异性自噬受体，它通过选择性自噬（ER-phagy）促进内质网（ER）降解。这种作用是由FAM134B与LC3和GABARAPL2的特异性相互作用介导的，LC3和GABARAPL2是小的泛素样自噬调节剂，对随后溶酶体降解的靶向和吞噬货物至关重要。在小鼠中，Fam134b的破坏导致内质网的扩张，内质网转换的抑制和感觉神经元的退化。因此，通过FAM134蛋白的选择性ER吞噬对于哺乳动物细胞稳态和控制ER形态和周转是必不可少的。该扩展提案将解决fam134b介导的细胞器转换的时间和定位以及er吞噬改变的下游影响。我们还将研究同源Fam134a和Fam134c基因在小鼠中破坏的表型后果以及这些基因在细胞器更新中的作用。

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.