Uncovering an Important Role for YopJ in the Inhibition of Caspase-1 in Activated Macrophages and Promoting Yersinia pseudotuberculosis Virulence

Abstract

Being the first line of defense against invading pathogens, the innate immune system has evolved to respond to general patterns of infection, termed pathogen-associated molecular patterns (PAMPs), via pattern recognition receptors (PRRs) (1, 2). Tolllike receptors (TLRs), acting as PRRs, detect distinct PAMPs from invading bacteria, such as flagellin (TLR5) and lipopolysaccharide (LPS; TLR4). Upon PAMP recognition, TLRs activate mitogenactivated protein kinase (MAPK) and nuclear factor-B (NF-B) pathways, which direct production of host-protective factors such as proinflammatory cytokines (3, 4). Bacterial pathogens produce virulence factors that inhibit PRR-directed innate immune responses in order to promote infection (5, 6). For example, numerous Gram-negative bacterial pathogens encode type III secretion systems (T3SSs) that are used to counteract host innate immune responses (7). During bacterium-host cell contact, T3SSs are activated and translocate effectors across the plasma membrane and into the eukaryotic cytosol. Translocated effectors inhibit innate immune responses and promote pathogenesis (7,8). In order to counteract infection by virulent pathogens, host cells can sense perturbations caused by T3SSs and/or effectors and produce heightened innate immune responses (9, 10).Disruptions induced by T3SSs and/or effectors in macrophages infected with bacterial pathogens commonly result in the activation of caspase-1 (11-14). Active caspase-1 promotes maturation and secretion of cytokines such as interleukin-1␤ (IL-1␤) and IL-18, which are produced as inactive precursors. Caspase-1 is also produced as a proenzyme, and its activation typically occurs in an inflammasome, a multioligomeric complex that serves as a molecular platform for the recruitment and auto-proteolytic cleavage of procaspase-1 (11-13, 15). Active caspase-1 also induces lysosome exocytosis and a form of inflammatory cell death, termed pyroptosis, which is characterized by osmotic swelling of the macrophage and subsequent rupture of the plasma membrane, resulting in the release of proinflammatory molecules (16). Several inflammasomes have been identified, and all but one (that formed by AIM2) contain proteins that are part of the nucleotidebinding domain leucine-rich repeat (NLR) family. These NLRs serve as cytosolic PRRs and are activated upon recognition of cytosolic PAMPs or danger signals (2,11,15). For some NLRs, such as NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) mediates inflammasome assembly by interacting with capase-1 and the NLR (11,13,15). Complexes of NLRs and ASC form large structures in macrophages that can be detected as foci by microscopic techniques (17)(18)(19). In cases where inflammasome assembly is

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

“…pestis is preventing production of active IL-1β and IL-18 through an apparent combination of activities [1,2,3,4,5,6]. Maturation of these major pro-inflammatory cytokines is primarily dependent on processing by the protease caspase-1.…”

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

“…However, Yersinia also inhibits inflammasome activation through the activities of YopK and YopM (36,38,39). Recent studies have revealed that YopJ can cooperate with YopM in activated macrophages to limit inflammasome activation (78,81), although YopJ blockade of NF-B and MAPK signaling triggers the activation of caspase-8 and caspase-1 in naive macrophages (82,83).…”

“…Successful bacterial pathogens have thus evolved strategies to mask these virulence factors from detection or to blunt the host response that is initiated (72)(73)(74). Indeed, a number of studies in several different systems have revealed that immune sensing of virulence factor activity promotes pathogen clearance (36,(75)(76)(77)(78)(79).…”

Identification of host factors required for Yersinia pestis macrophage intracellular survival and their impact on vacuole maturation, acidification and trafficking.

“…pestis infection produces very little pro-inflammatory response early during infection, but at latter stages there is a dramatic spike in inflammation [1,[316][317][318][319][320][321][322]. This phenomena is also observed in transcritpome analysis of monocytes/ macrophages infected with Y. pestis lacking the pCD1 virulence plasmid and T3SS secreted Yops [321], which are potent modulators of the inflammasome and pro-inflammatory apoptosis [323][324][325]. Rab11 trafficking has also been shown to impact many host proteins involved in innate immunity.…”