PMID:23422410

Citation	de Jong, MF, Starr, T, Winter, MG, den Hartigh, AB, Child, R, Knodler, LA, van Dijl, JM, Celli, J and Tsolis, RM (2013) Sensing of bacterial type IV secretion via the unfolded protein response. MBio 4:e00418-12
Abstract	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.
Links	PubMed PMC3624511 Online version:10.1128/mBio.00418-12
Keywords	Animals; Bacterial Secretion Systems; Brucella abortus/metabolism; Brucella abortus/pathogenicity; Cytokines/secretion; Endoplasmic Reticulum/drug effects; Endoplasmic Reticulum/ultrastructure; Female; HeLa Cells; Humans; Inflammation Mediators/metabolism; Macrophages; Mice; Mice, Inbred C57BL; Unfolded Protein Response; Virulence Factors/metabolism; Virulence Factors/toxicity
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
BRUA2:Q2YQ34		GO:0044165: host cell endoplasmic reticulum	ECO:0000314:		C		Figure 4. Localization of HA-VceC (BAB1_1058) fusions in HeLa cells (A to C) and RAW264.7 macrophages (D). Transfected cells grown on coverslips were stained with anti-calreticulin antibody (red) to visualize the ER (A, B, and D)or with phalloidin (red) to visualize the actin cytoskeleton (C). HA-VceC was visualized with anti-HA antibody (green). The images shown are representative of at least three independent experiments.	complete CACAO 11039
BRUA2:Q2YQ34		GO:0034976: response to endoplasmic reticulum stress	ECO:0000314:		P		Figure 6 and 7. Shows that VceC produces ER stress.	complete CACAO 11040

References

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