3 years ago

Guanylate Binding Proteins regulate inflammasome activation in response to hyper-injected Yersinia translocon components.

Feeley E, Zwack EE, Burton AR, Brodsky IE, Kanneganti TD, Bliska JB, Yamamoto M, Hu B, Coers J
Gram-negative bacterial pathogens utilize virulence-associated secretion systems to inject, or translocate, effector proteins into host cells to manipulate cellular processes and promote bacterial replication. However, translocated bacterial products are sensed by Nucleotide Binding Domain and Leucine Rich Repeat containing proteins (NLRs), which trigger formation of a multi-protein complex called the inflammasome, leading to secretion of IL-1 family cytokines, pyroptosis, and control of pathogen replication. Pathogenic Yersinia inject effector proteins termed Yops, as well as pore-forming proteins that comprise the translocon itself, into target cells. The Yersinia translocation regulatory protein YopK promotes bacterial virulence by limiting hyper-injection of the translocon proteins YopD and YopB into cells, thereby limiting cellular detection of Yersinia virulence activity. How hyper-injection of translocon proteins leads to inflammasome activation is currently unknown. We found that translocated YopB and YopD colocalize with the late endosomal/lysosomal protein LAMP1, and that frequency of YopD and LAMP1 association correlated with caspase-1 activation in individual cells. We also observed colocalization between YopD and galectin-3, an indicator of endosomal membrane damage. Intriguingly, YopK limited the colocalization of galectin-3 with YopD, suggesting that YopK limits induction or sensing of endosomal membrane damage by components of the T3SS translocon. Furthermore, Guanylate Binding Proteins (GBPs) on chromosome 3 (GbpChr3 ), which respond to pathogen-induced damage or alteration of host membranes, were necessary for inflammasome activation in response to hyper-injected YopB/D. Our findings indicate that lysosomal damage by Yersinia translocon proteins promotes inflammasome activation and implicate GBPs as key regulators of this process.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28784930

DOI: PubMed:28784930

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