A reversible phospho-switch mediated by ULK1 regulates the activity of autophagy protease ATG4B.
A reversible phospho-switch mediated by ULK1 regulates the activity of autophagy protease ATG4B.
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DOI：
10.1038/s41467-017-00303-2
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发表时间：
2017-08-18
影响因子：
16.6
通讯作者：
Ketteler R
中科院分区：
文献类型：
--
作者：
Pengo N;Agrotis A;Prak K;Jones J;Ketteler R
自噬诱导后，泛素样蛋白LC3与自噬体内外膜上的磷脂酰乙醇胺（PE）偶联，允许货物选择和自噬体形成。LC3经过两个加工步骤，前LC3的蛋白水解裂解和LC3- pe自噬体的去脂化，这两个过程都是由相同的半胱氨酸蛋白酶ATG4完成的。目前尚不清楚ATG4的活动是如何调节以协调这些事件的。在这里，我们发现ULK1，一种在自噬体形成位点活化的蛋白激酶，磷酸化人类ATG4B的丝氨酸316。磷酸化在这个残基导致抑制其催化活性在体外和体内。另一方面，磷酸酶PP2A-PP2R3B可以去除这种抑制性磷酸化。我们提出，ulk1介导的磷酸化和pp2a介导的去磷酸化的相反活性提供了一个磷酸化开关，调节ATG4B的细胞活性来控制LC3加工。自噬诱导后，LC3被蛋白酶ATG4切割并偶联到自噬体膜上；然而，它的去除是由相同的蛋白酶介导的。本文作者表明，ulk1介导的ATG4磷酸化和pp2a介导的ATG4去磷酸化调节其细胞活性，从而控制LC3加工。
Upon induction of autophagy, the ubiquitin-like protein LC3 is conjugated to phosphatidylethanolamine (PE) on the inner and outer membrane of autophagosomes to allow cargo selection and autophagosome formation. LC3 undergoes two processing steps, the proteolytic cleavage of pro-LC3 and the de-lipidation of LC3-PE from autophagosomes, both executed by the same cysteine protease ATG4. How ATG4 activity is regulated to co-ordinate these events is currently unknown. Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316. Phosphorylation at this residue results in inhibition of its catalytic activity in vitro and in vivo. On the other hand, phosphatase PP2A-PP2R3B can remove this inhibitory phosphorylation. We propose that the opposing activities of ULK1-mediated phosphorylation and PP2A-mediated dephosphorylation provide a phospho-switch that regulates the cellular activity of ATG4B to control LC3 processing. Upon autophagy induction, LC3 is cleaved by the protease ATG4 and conjugated to the autophagosomal membrane; however, its removal is mediated by the same protease. Here the authors show that ULK1-mediated phosphorylation and PP2A-mediated dephosphorylation of ATG4 regulates its cellular activity to control LC3 processing.
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影响因子：
30.3
作者：
Randow F;Youle RJ
通讯作者：
Youle RJ
影响因子：
16.6
作者：
Sánchez-Wandelmer J;Kriegenburg F;Rohringer S;Schuschnig M;Gómez-Sánchez R;Zens B;Abreu S;Hardenberg R;Hollenstein D;Gao J;Ungermann C;Martens S;Kraft C;Reggiori F
通讯作者：
Reggiori F
影响因子：
3.3
作者：
Jung, Chang Hwa;Jun, Chang Bong;Kim, Do-Hyung
通讯作者：
Kim, Do-Hyung
影响因子：
4.8
作者：
Olsvik, Hallvard L.;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
3.3
作者：
Fujita, Naonobu;Hayashi-Nishino, Mitsuko;Yoshimori, Tamotsu
通讯作者：
Yoshimori, Tamotsu