Journal
CELL REPORTS
Volume 37, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109894
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Funding
- HHMI
- NIAID [R01 AI113211, R01 AI146245]
- DFG [AU550/1-1]
- NIH from NIGMS [1R15GM143733]
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The study investigated the mechanism of intracellular growth of Legionella pneumophila and found that SdhA interacts with OCRL, affecting endosomal dynamics and interfering with endosomal trafficking, resulting in changes in intracellular growth.
Legionella pneumophila grows intracellularly within a replication vacuole via action of lcm/Dot-secreted proteins. One such protein, SdhA, maintains the integrity of the vacuolar membrane, thereby preventing cytoplasmic degradation of bacteria. We show here that SdhA binds and blocks the action of OCRL (OculoCerebroRenal syndrome of Lowe), an inositol 5-phosphatase pivotal for controlling endosomal dynamics. OCRL depletion results in enhanced vacuole integrity and intracellular growth of a sdhA mutant, consistent with OCRL participating in vacuole disruption. Overexpressed SdhA alters OCRL function, enlarging endosomes, driving endosomal accumulation of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P-2), and interfering with endosomal trafficking. SdhA interrupts Rab guanosine triphosphatase (GTPase)-OCRL interactions by binding to the OCRL ASPM-SPD2-Hydin (ASH) domain, without directly altering OCRL 5-phosphatase activity. The Legionella vacuole encompassing the sdhA mutant accumulates OCRL and endosomal antigen EEA1 (Early Endosome Antigen 1), consistent with SdhA blocking accumulation of OCRL-containing endosomal vesicles. Therefore, SdhA hijacking of OCRL is associated with blocking trafficking events that disrupt the pathogen vacuole.
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