The many faces of the YopM effector from plague causative bacterium Yersinia pestis and its implications for host immune modulation

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Abstract
The Yersinia outer protein (Yop) M effector from the Yersinia pestis bacterium is well-known for being a critical virulence determinant; however, structural insight vis-à-vis its role in Y. pestis pathogenesis has been elusive. Here, we investigate the intact sequence of the YopM protein through our recently developed fold identification and homology modeling tools, and analyze the immune modulatory potential of its constituent domains. We identify a putative novel E3 ligase (NEL) domain towards the C-terminal tail of YopM and characterize its active site, to show that YopM could function as an autoregulated bacterial type E3 ubiquitin ligase. We further identify unreported NEL domains in several other bacteria and note remarkable similarity in sequence, structure, surface, and electrostatics for the family of NEL-containing bacterial effectors that suggests conserved function and potentially similar host targets for these proteins. Based on these observations and recent empirical evidence for degradation of the human proteins HLA-DR, thioredoxin, and NEMO/IKKγ by other members of the NEL-containing bacterial family, we discuss the potential for YopM to modulate a wide spectrum of immune signal transduction pathways. The key immune modulatory effects highlighted are suppression of MHC class II antigen presentation, dampening of nuclear factor (NF)-κB mediated inflammatory response, and intonation of mitogen-activated protein kinase (MAPK) signaling. Additionally, our analysis of the modeled YopM LRR domain reveals structural features akin to the Toll-like receptor 4 (TLR4) LRR motif. We propose that YopM LRR could be a ‘molecular mimic’ of TLR4 LRR, permitting reduced immunogenicity and potentially mitigating bacterial lipopolysaccharide surveillance of the innate immune system. Our identification and characterization of the YopM NEL domain, taken together with our analysis of the YopM LRR domain, provides plausible insight into subversion of host immunity by Y. pestis YopM and perhaps could set the stage for design of new therapeutic opportunities.

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