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<p><i>Legionella pneumophila</i> is an intracellular pathogen that causes Legionnaires’ disease. The bacteria release effector proteins, some of which remodel host autophagic-lysosomal pathways. One such effector is RavZ, which delipidates ATG8 proteins, making compromising autophagy in Legionella-infected cells. Here we show that SidE effectors also affect these pathways, by mediating phosphoribosyl-ubiquitination (PR-Ub) of the autophagic SNARE proteins STX17 and SNAP29. STX17 modification induces recruitment of STX17-positive membranes from the endoplasmic reticulum to Legionella-containing phagosomes, forming replicative vacuoles. Using proximity labeling, biochemistry and Legionella infection studies, we define a mechanism by which autophagy is hijacked by bacteria to recruit ER membranes to the bacterial vacuole, via a structure bearing autophagy markers but not fusing with lysosomes. Mass-spectrometric identification of PR-Ub sites and mutational studies show that phosphoribosyl-ubiquitination of STX17 alters its interaction with ATG14L, which causes ER membranes to be recruited to the bacterial vacuole in a PI3K-dependent manner. On the other hand, phosphoribosyl-ubiquitination of SNAP29 inhibits the formation of the autophagosomal SNARE complex (STX17-SNAP29-VAMP8) via steric hindrance, thus preventing the fusion of bacterial vacuoles with lysosomes.</p>

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Phosphoribosyl ubiquitination of SNARE proteins regulates autophagy during Legionella infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月12日

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  • Rukmini Mukherjee,
  • Anshu Bhattacharya,
  • Ines Tomaskovic,
  • João Mello-Vieira,
  • Melinda Elaine Brunstein,
  • Marion Başoğlu,
  • Tineke Veenendaal,
  • Henry Bailey,
  • Thomas Colby,
  • Mohit Misra,
  • Stefan Eimer,
  • Judith Klumperman,
  • Christian Münch,
  • Ivan Matic,
  • Ivan Dikic

摘要

Legionella pneumophila is an intracellular pathogen that causes Legionnaires’ disease. The bacteria release effector proteins, some of which remodel host autophagic-lysosomal pathways. One such effector is RavZ, which delipidates ATG8 proteins, making compromising autophagy in Legionella-infected cells. Here we show that SidE effectors also affect these pathways, by mediating phosphoribosyl-ubiquitination (PR-Ub) of the autophagic SNARE proteins STX17 and SNAP29. STX17 modification induces recruitment of STX17-positive membranes from the endoplasmic reticulum to Legionella-containing phagosomes, forming replicative vacuoles. Using proximity labeling, biochemistry and Legionella infection studies, we define a mechanism by which autophagy is hijacked by bacteria to recruit ER membranes to the bacterial vacuole, via a structure bearing autophagy markers but not fusing with lysosomes. Mass-spectrometric identification of PR-Ub sites and mutational studies show that phosphoribosyl-ubiquitination of STX17 alters its interaction with ATG14L, which causes ER membranes to be recruited to the bacterial vacuole in a PI3K-dependent manner. On the other hand, phosphoribosyl-ubiquitination of SNAP29 inhibits the formation of the autophagosomal SNARE complex (STX17-SNAP29-VAMP8) via steric hindrance, thus preventing the fusion of bacterial vacuoles with lysosomes.