The Yersinia Type III secretion effector YopM Is an E3 ubiquitin ligase that induced necrotic cell death by targeting NLRP3

Abstract

Yersinia pestis uses type III effector proteins to target eukaryotic signaling systems. The Yersinia outer protein (Yop) M effector from the Y. pestis strain is a critical virulence determinant; however, its role in Y. pestis pathogenesis is just beginning to emerge. Here we first identify YopM as the structural mimic of the bacterial IpaH E3 ligase family in vitro, and establish that the conserved CLD motif in its N-terminal is responsible for the E3 ligase function. Furthermore, we show that NLRP3 is a novel target of the YopM protein. Specially, YopM associates with NLRP3, and its CLD ligase motif mediates the activating K63-linked ubiquitylation of NLRP3; as a result, YopM modulates NLRP3-mediated cell necrosis. Mutation of YopM E3 ligase motif dramatically reduces the ability of Y. pestis to induce HMGB1 release and cell necrosis, which ultimately contributes to bacterial virulence. In conclusion, this study has identified a previously unrecognized role for YopM E3 ligase activity in the regulation of host cell necrosis and plague pathogenesis.

Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

“…This idea was supported by Han et al (41) and Song et al (15), although they identified different ubiquitinases as operative compared with those identified by Yan et al In addition, Py et al (14) showed that deubiquitination of both K63-and K48-linked polyubiquitin chains was required for NLRP3 inflammasome activation. A somewhat different view of the role of polyubiquitination in NLRP3 activation was suggested by Wei et al (42), who showed that the Yersinia-type III secretion effector YopM promoted K63-linked polyubiquitination and activation of NLRP3; thus, in this case, K63-linked polyubiquitination was shown to be a positive regulator of the NLRP3 inflammasome. Our data showed that interaction of intact CARD8 with NLRP3 results in reduced K63-and K48-linked polyubiquitination of NLRP3; these data thus support the idea that intact CARD8 acts as a negative regulator of NLRP3, at least in part by its ability to promote NLRP3 K63-and K48-linked polyubiquitination.…”

Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins

“…Yersinia outer protein M (YopM) possesses a LPX-type domain and traffic to the nucleus [80,81]. However, although it has been proposed to function as an E3 ubiquitin ligase for one particular strain of Y. pestis [82], YopM does not possess an NEL domain and appears to rather act as a scaffolding protein facilitating the formation of a complex between its targets, the serine/threonine kinases RSK1 and PKN2 [83,84]. YopM causes enhanced phosphorylation of RSK1 in the nucleus, leading to enhanced transcription of immunosuppressive cytokine genes, such as IL-10 [85].…”

“…[ [80][81][82][83][84][85][86] The shaded parts are to better separate the different bacterial species.…”

The species-spanning family of LPX-motif harbouring effector proteins

“…Because of lacking the C‐terminal NEL domain, YopM appears to be an outlier in the LPX effector family. Nevertheless, authors of a recent study claim that due to a conserved Cys‐Leu‐Asp amino acid, sequence motif within the N‐terminal α‐helical region of Yersinia pestis YopM functions as an E3 ubiquitin ligase, too (Wei et al, ), which, however appears to be restricted to this particular YopM of this strain of Y . pestis .…”