Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
Instituto Universitario de Oncología (IUOPA), Asturias, Spain.
Cell Death Differ. 2021 Sep;28(9):2651-2672. doi: 10.1038/s41418-021-00776-1. Epub 2021 Apr 1.
Despite the great advances in autophagy research in the last years, the specific functions of the four mammalian Atg4 proteases (ATG4A-D) remain unclear. In yeast, Atg4 mediates both Atg8 proteolytic activation, and its delipidation. However, it is not clear how these two roles are distributed along the members of the ATG4 family of proteases. We show that these two functions are preferentially carried out by distinct ATG4 proteases, being ATG4D the main delipidating enzyme. In mammalian cells, ATG4D loss results in accumulation of membrane-bound forms of mATG8s, increased cellular autophagosome number and reduced autophagosome average size. In mice, ATG4D loss leads to cerebellar neurodegeneration and impaired motor coordination caused by alterations in trafficking/clustering of GABA receptors. We also show that human gene variants of ATG4D associated with neurodegeneration are not able to fully restore ATG4D deficiency, highlighting the neuroprotective role of ATG4D in mammals.
尽管近年来自噬研究取得了重大进展，但四种哺乳动物 Atg4 蛋白酶（ATG4A-D）的具体功能仍不清楚。在酵母中，Atg4 介导 Atg8 蛋白的蛋白水解激活及其去脂化。然而，目前尚不清楚这两个角色如何沿着 Atg4 蛋白酶家族成员分布。我们发现这两种功能主要由不同的 Atg4 蛋白酶执行，其中 ATG4D 是主要的去脂酶。在哺乳动物细胞中，ATG4D 的缺失会导致膜结合形式的 mATG8 积累，细胞内自噬体数量增加，自噬体平均大小减小。在小鼠中，ATG4D 的缺失会导致小脑神经退行性变和运动协调能力受损，这是由于 GABA 受体的运输/聚集发生改变所致。我们还表明，与神经退行性变相关的人类 ATG4D 基因突变不能完全恢复 ATG4D 的缺乏，这突出了 ATG4D 在哺乳动物中的神经保护作用。
