The formation of the LCV is a complex process governed by the Icm/Dot type IV secretion system (T4SS). This T4SS injects more than 300 different “effector” proteins into the host cell, dictating every step from uptake to interference with various vesicle trafficking pathways and autophagy, interaction with the ER, and finally escape from the host cell (Finsel and Hilbi, 2015; Ensminger, 2016).
To this end, the Icm/Dot-translocated proteins subvert numerous host cell targets, including PI lipids, which are used by several effectors as membrane anchors, and small GTPases (Haneburger and Hilbi, 2013; Rothmeier et al., 2013; Finsel and Hilbi, 2015). LCVs avoid luminal acidification and fusion with lysosomes, but continuously and extensively communicate with multiple vesicle trafficking routes (Horwitz, 1983; Urwyler et al., 2009a; Xu et al., 2010; Zhao et al., 2017).
Interaction with the endocytic pathway is indicated by the presence of the small GTPases Rab5a, Rab7a, and Rab21 on the LCV membrane (Urwyler et al., 2009b; Hoffmann et al., 2014a).
Moreover, LCVs acquire PtdIns(3)P within 1 min of bacterial uptake, and gradually lose this PI lipid within 2 h (Weber et al., 2014).
In the endocytic pathway, PtdIns(3)P is a crucial regulator, necessary for recruitment of early endosomal antigen 1 (EEA1) and for downstream events leading to fusion of the phagosome with bactericidal lysosomes (Stenmark, 2009).
A hallmark of LCV maturation is the intimate interaction of the pathogen vacuole with the ER (Swanson and Isberg, 1995; Lu and Clarke, 2005; Robinson and Roy, 2006), as a consequence of Rab1-dependent recruitment of secretory vesicles at ER exit sites (Kagan and Roy, 2002; Arasaki and Roy, 2010; Arasaki et al., 2012).
PtdIns(4)P is a major regulator of secretory vesicle trafficking through the Golgi apparatus (Jean and Kiger, 2012), required for late steps of endocytosis (Jeschke et al., 2015) and present on LCVs (Weber et al., 2006, 2014).
In fact, PtdIns(4)P transiently localizes to LCVs independently of the Icm/Dot T4SS immediately following bacterial uptake, but is then rapidly cleared. Over the following 2 h, PtdIns(4)P again accumulates on LCVs in an Icm/Dot-dependent manner, preceding attachment of the ER (Weber et al., 2014).
In addition to Rab1, several other small GTPases involved in the secretory pathway are present on the LCV (Urwyler et al., 2009b; Hoffmann et al., 2014a). Of these, Rab8a, Rab10, and Rab32, all implicated in Golgi to endosome trafficking, promote intracellular replication of L. pneumophila (Hoffmann et al., 2014a). Thus, L. pneumophila exploits the secretory trafficking pathway to promote formation of the replication-permissive LCV.
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Legionellalla on tosi legionsa effektoreja: https://www.sciencedirect.com/science/article/abs/pii/S1369527415001575
- Highlights
- Legionella pneumophila has the largest known bacterial arsenal of effector proteins (330+).Extensive functional redundancy exists between effectors and may result from host cycling.Metaeffectors (effectors that directly regulate other effectors) may contribute to the expansion.Selection against effector expansion may be absent in the pathogen's natural hosts.Promiscuous translocation may favor evolution of new effectors.
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