Salmonella effectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways

Joshua Newson, Nichollas E. Scott, Ivy Yeuk Wah Chung, Tania Wong Fok Lung, Cristina Giogha, Jiyao Gan, Nancy Wang, Richard Strugnell, Nathaniel F. Brown, Miroslaw Cygler, Jaclyn Pearson, Elizabeth Hartland

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Strains of Salmonella utilize two distinct type three secretion systems to deliver effector proteins directly into host cells. The Salmonella effectors SseK1 and SseK3 are arginine glycosyltransferases that modify mammalian death domain containing proteins with N-acetyl glucosamine (GlcNAc) when overexpressed ectopically or as recombinant protein fusions. Here, we combined Arg-GlcNAc gly-copeptide immunoprecipitation and mass spectrometry to identify host proteins GlcNAcylated by endogenous levels of SseK1 and SseK3 during Salmonella infection. We observed that SseK1 modified the mammalian signaling protein TRADD, but not FADD as previously reported. Overexpression of SseK1 greatly broadened substrate specificity, whereas ectopic co-expression of SseK1 and TRADD increased the range of modified arginine residues within the death domain of TRADD. In contrast, endogenous levels of SseK3 resulted in modification of the death domains of receptors of the mammalian TNF superfamily, TNFR1 and TRAILR, at residues Arg376 and Arg293 respectively. Structural studies on SseK3 showed that the enzyme displays a classic GT-A glycosyltransferase fold and binds UDP-GlcNAc in a narrow and deep cleft with the GlcNAc facing the surface. Together our data suggest that salmonellae carrying sseK1 and sseK3 employ the glycosyltransferase effectors to antagonise different components of death receptor signaling.

Original languageEnglish
Pages (from-to)1138-1156
Number of pages19
JournalMolecular & Cellular Proteomics
Volume18
Issue number6
DOIs
Publication statusPublished - 1 Jun 2019

Cite this

Newson, Joshua ; Scott, Nichollas E. ; Chung, Ivy Yeuk Wah ; Lung, Tania Wong Fok ; Giogha, Cristina ; Gan, Jiyao ; Wang, Nancy ; Strugnell, Richard ; Brown, Nathaniel F. ; Cygler, Miroslaw ; Pearson, Jaclyn ; Hartland, Elizabeth. / Salmonella effectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways. In: Molecular & Cellular Proteomics. 2019 ; Vol. 18, No. 6. pp. 1138-1156.
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title = "Salmonella effectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways",
abstract = "Strains of Salmonella utilize two distinct type three secretion systems to deliver effector proteins directly into host cells. The Salmonella effectors SseK1 and SseK3 are arginine glycosyltransferases that modify mammalian death domain containing proteins with N-acetyl glucosamine (GlcNAc) when overexpressed ectopically or as recombinant protein fusions. Here, we combined Arg-GlcNAc gly-copeptide immunoprecipitation and mass spectrometry to identify host proteins GlcNAcylated by endogenous levels of SseK1 and SseK3 during Salmonella infection. We observed that SseK1 modified the mammalian signaling protein TRADD, but not FADD as previously reported. Overexpression of SseK1 greatly broadened substrate specificity, whereas ectopic co-expression of SseK1 and TRADD increased the range of modified arginine residues within the death domain of TRADD. In contrast, endogenous levels of SseK3 resulted in modification of the death domains of receptors of the mammalian TNF superfamily, TNFR1 and TRAILR, at residues Arg376 and Arg293 respectively. Structural studies on SseK3 showed that the enzyme displays a classic GT-A glycosyltransferase fold and binds UDP-GlcNAc in a narrow and deep cleft with the GlcNAc facing the surface. Together our data suggest that salmonellae carrying sseK1 and sseK3 employ the glycosyltransferase effectors to antagonise different components of death receptor signaling.",
author = "Joshua Newson and Scott, {Nichollas E.} and Chung, {Ivy Yeuk Wah} and Lung, {Tania Wong Fok} and Cristina Giogha and Jiyao Gan and Nancy Wang and Richard Strugnell and Brown, {Nathaniel F.} and Miroslaw Cygler and Jaclyn Pearson and Elizabeth Hartland",
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doi = "10.1074/mcp.RA118.001093",
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Newson, J, Scott, NE, Chung, IYW, Lung, TWF, Giogha, C, Gan, J, Wang, N, Strugnell, R, Brown, NF, Cygler, M, Pearson, J & Hartland, E 2019, 'Salmonella effectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways' Molecular & Cellular Proteomics, vol. 18, no. 6, pp. 1138-1156. https://doi.org/10.1074/mcp.RA118.001093

Salmonella effectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways. / Newson, Joshua; Scott, Nichollas E.; Chung, Ivy Yeuk Wah ; Lung, Tania Wong Fok; Giogha, Cristina; Gan, Jiyao; Wang, Nancy; Strugnell, Richard ; Brown, Nathaniel F.; Cygler, Miroslaw; Pearson, Jaclyn; Hartland, Elizabeth.

In: Molecular & Cellular Proteomics, Vol. 18, No. 6, 01.06.2019, p. 1138-1156.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Salmonella effectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways

AU - Newson, Joshua

AU - Scott, Nichollas E.

AU - Chung, Ivy Yeuk Wah

AU - Lung, Tania Wong Fok

AU - Giogha, Cristina

AU - Gan, Jiyao

AU - Wang, Nancy

AU - Strugnell, Richard

AU - Brown, Nathaniel F.

AU - Cygler, Miroslaw

AU - Pearson, Jaclyn

AU - Hartland, Elizabeth

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