Abstract：
Xenophagy is an evolutionarily conserved host defensive mechanism to eliminate invading microorganisms through autophagic machinery. The intracellular bacterial pathogen Legionella pneumophila can avoid clearance by the xenophagy pathway via the actions of multiple Dot/Icm effector proteins. Previous studies have shown that p62, an adaptor protein involved in xenophagy signaling, is excluded from Legionella-containing vacuoles (LCVs). Such defects are attributed to the multifunctional SidE family effectors (SidEs) that exhibit classic deubiquitinase (DUB) and phosphoribosyl ubiquitination (PR-ubiquitination) activities, yet the mechanism remains elusive. In the present study, we demonstrate that the host DUB USP14 is PR-ubiquitinated by SidEs at multiple serine residues, which impairs its DUB activity and its interactions with p62. The exclusion of p62 from the bacterial phagosome requires the ubiquitin ligase but not the DUB activity of SidEs. These results reveal that PR-ubiquitination of USP14 by SidEs contributes to the evasion of xenophagic clearance by L. pneumophila.
摘要：
异种吞噬是一种进化上保守的宿主防御机制，通过自噬机制消灭入侵的微生物。细胞内细菌病原体嗜肺军团菌可以通过多种Dot/Icm效应蛋白的作用避免异种吞噬途径的清除。以前的研究表明，p62，一种参与异种吞噬信号传导的衔接蛋白，从含军团菌的液泡(LCV)中排除。这些缺陷归因于多功能SidE家族效应子（SidEs），其表现出经典的去泛素化酶（DUB）和磷酸核糖泛素化（PR-泛素化）活性，然而，机制仍然难以捉摸。在本研究中,我们证明了宿主DUBUSP14在多个丝氨酸残基处被SidEs泛素化，这会损害其DUB活性及其与p62的相互作用。从细菌吞噬体中排除p62需要泛素连接酶，但不需要SidEs的DUB活性。这些结果表明，SidEs对USP14的PR泛素化有助于逃避嗜肺乳杆菌的异种清除。
