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Sensing of Bacterial Type IV Secretion via the Unfolded Protein Response

de Jong, M. F., Starr, T., Winter, M. G., den Hartigh, A. B., Child, R., Knodler, L. A., van Dijl, J. M., Celli, J. & Tsolis, R. M., 2013, In : Mbio. 4, 1, 10 p., e00418-12.

Research output: Contribution to journalArticleAcademicpeer-review

  • Maarten F. de Jong
  • Tregei Starr
  • Maria G. Winter
  • Andreas B. den Hartigh
  • Robert Child
  • Leigh A. Knodler
  • Jan Maarten van Dijl
  • Jean Celli
  • Renee M. Tsolis

Host cytokine responses to Brucella abortus infection are elicited predominantly by the deployment of a type IV secretion system (T4SS). However, the mechanism by which the T4SS elicits inflammation remains unknown. Here we show that translocation of the T4SS substrate VceC into host cells induces proinflammatory responses. Ectopically expressed VceC interacted with the endoplasmic reticulum (ER) chaperone BiP/Grp78 and localized to the ER of HeLa cells. ER localization of VceC required a transmembrane domain in its N terminus. Notably, the expression of VceC resulted in reorganization of ER structures. In macrophages, VceC was required for B. abortus-induced inflammation by induction of the unfolded protein response by a process requiring inositol-requiring transmembrane kinase/endonuclease 1. Altogether, these findings suggest that translocation of the T4SS effector VceC induces ER stress, which results in the induction of proinflammatory host cell responses during B. abortus infection.

IMPORTANCE Brucella species are pathogens that require a type IV secretion system (T4SS) to survive in host cells and to maintain chronic infection. By as-yet-unknown pathways, the T4SS also elicits inflammatory responses in infected cells. Here we show that inflammation caused by the T4SS results in part from the sensing of a T4SS substrate, VceC, that localizes to the endoplasmic reticulum (ER), an intracellular site of Brucella replication. Possibly via binding of the ER chaperone BiP, VceC causes ER stress with concomitant expression of proinflammatory cytokines. Thus, induction of the unfolded protein response may represent a novel pathway by which host cells can detect pathogens deploying a T4SS.

Original languageEnglish
Article numbere00418-12
Number of pages10
JournalMbio
Volume4
Issue number1
Publication statusPublished - 2013

    Keywords

  • NF-KAPPA-B, ENDOPLASMIC-RETICULUM STRESS, BRUCELLA-ABORTUS INFECTION, CHAIN BINDING-PROTEIN, INNATE IMMUNE-SYSTEM, TRANSCRIPTION FACTOR, INTRACELLULAR REPLICATION, MESSENGER-RNA, VIRB MUTANT, ER STRESS

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