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Bacterial effectors and their functions in the ubiquitin-proteasome system: insight from the modes of substrate recognition.

Kim M, Otsubo R, Morikawa H, Nishide A, Takagi K, Sasakawa C, Mizushima T - Cells (2014)

Bottom Line: Modulation of the host ubiquitin system by bacterial effector proteins inhibits innate immune responses and hijacks central signaling pathways.Bacterial effectors mimic enzymes of the host ubiquitin system, but may or may not be structurally similar to the mammalian enzymes.Other effectors bind and modify components of the host ubiquitin system, and some are themselves subject to ubiquitination.

View Article: PubMed Central - PubMed

Affiliation: Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai 4-6-1, Minato-ku 4-6-1, Tokyo 108-8639, Japan. minsoo@ims.u-tokyo.ac.jp.

ABSTRACT
Protein ubiquitination plays indispensable roles in the regulation of cell homeostasis and pathogenesis of neoplastic, infectious, and neurodegenerative diseases. Given the importance of this modification, it is to be expected that several pathogenic bacteria have developed the ability to utilize the host ubiquitin system for their own benefit. Modulation of the host ubiquitin system by bacterial effector proteins inhibits innate immune responses and hijacks central signaling pathways. Bacterial effectors mimic enzymes of the host ubiquitin system, but may or may not be structurally similar to the mammalian enzymes. Other effectors bind and modify components of the host ubiquitin system, and some are themselves subject to ubiquitination. This review will describe recent findings, based on structural analyses, regarding how pathogens use post-translational modifications of proteins to establish an infection.

No MeSH data available.


Related in: MedlinePlus

Novel E3 ligase (NEL) family ubiquitin ligases. (A) SspH1 is secreted into host cells by Salmonella T3SS SPI-1 and SPI-2. The leucine-rich repeat (LRR) domain of SspH1 recognizes and interacts with the homology region 1b (HR1b) coiled-coil subdomain of protein kinase N1 (PKN1). PKN1 is ubiquitinated and degraded by SspH1, resulting in down-regulation of androgen receptor (AR) signaling. In the cytoplasm, AR (in complex with heat shock proteins 70 and 90) interacts with ligands such as testosterone, and then translocates to the nucleus to act as a transcription factor; (B) SspH1-PKN1 interaction surface.The figure illustrates the crystal structure of the LRR of SspH1 in complex with the HR1b of PKN1 (cyan) (PDB ID 4NKG). Protein surface and cartoon representation of SspH1 are shown in gray and orange, respectively. H392 of SspH1 is shown in magenta. The contact interface between LRR and NEL is indicated by a dashed oval. The molecular graphics were prepared using PyMOL [76].
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cells-03-00848-f002: Novel E3 ligase (NEL) family ubiquitin ligases. (A) SspH1 is secreted into host cells by Salmonella T3SS SPI-1 and SPI-2. The leucine-rich repeat (LRR) domain of SspH1 recognizes and interacts with the homology region 1b (HR1b) coiled-coil subdomain of protein kinase N1 (PKN1). PKN1 is ubiquitinated and degraded by SspH1, resulting in down-regulation of androgen receptor (AR) signaling. In the cytoplasm, AR (in complex with heat shock proteins 70 and 90) interacts with ligands such as testosterone, and then translocates to the nucleus to act as a transcription factor; (B) SspH1-PKN1 interaction surface.The figure illustrates the crystal structure of the LRR of SspH1 in complex with the HR1b of PKN1 (cyan) (PDB ID 4NKG). Protein surface and cartoon representation of SspH1 are shown in gray and orange, respectively. H392 of SspH1 is shown in magenta. The contact interface between LRR and NEL is indicated by a dashed oval. The molecular graphics were prepared using PyMOL [76].

Mentions: Salmonella SspH1, another NEL family member, induces protein kinase N1 (PKN1) degradation in a ubiquitin- and proteasome-dependent manner [36]. PKN1 interacts with androgen receptor (AR), functions as a transcriptional coactivator, and regulates a wide range of cellular processes including cytoskeletal regulation, tumorigenesis, and transcription [74,75]. In 293T cells, expression of wild-type SspH1, but not E3 ligase-dead or SspH1-PKN1 interface mutants, suppresses the AR-responsive element [37]. Degradation of PKN1 by SspH1 attenuates the AR response (Figure 2A).


Bacterial effectors and their functions in the ubiquitin-proteasome system: insight from the modes of substrate recognition.

Kim M, Otsubo R, Morikawa H, Nishide A, Takagi K, Sasakawa C, Mizushima T - Cells (2014)

Novel E3 ligase (NEL) family ubiquitin ligases. (A) SspH1 is secreted into host cells by Salmonella T3SS SPI-1 and SPI-2. The leucine-rich repeat (LRR) domain of SspH1 recognizes and interacts with the homology region 1b (HR1b) coiled-coil subdomain of protein kinase N1 (PKN1). PKN1 is ubiquitinated and degraded by SspH1, resulting in down-regulation of androgen receptor (AR) signaling. In the cytoplasm, AR (in complex with heat shock proteins 70 and 90) interacts with ligands such as testosterone, and then translocates to the nucleus to act as a transcription factor; (B) SspH1-PKN1 interaction surface.The figure illustrates the crystal structure of the LRR of SspH1 in complex with the HR1b of PKN1 (cyan) (PDB ID 4NKG). Protein surface and cartoon representation of SspH1 are shown in gray and orange, respectively. H392 of SspH1 is shown in magenta. The contact interface between LRR and NEL is indicated by a dashed oval. The molecular graphics were prepared using PyMOL [76].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4197628&req=5

cells-03-00848-f002: Novel E3 ligase (NEL) family ubiquitin ligases. (A) SspH1 is secreted into host cells by Salmonella T3SS SPI-1 and SPI-2. The leucine-rich repeat (LRR) domain of SspH1 recognizes and interacts with the homology region 1b (HR1b) coiled-coil subdomain of protein kinase N1 (PKN1). PKN1 is ubiquitinated and degraded by SspH1, resulting in down-regulation of androgen receptor (AR) signaling. In the cytoplasm, AR (in complex with heat shock proteins 70 and 90) interacts with ligands such as testosterone, and then translocates to the nucleus to act as a transcription factor; (B) SspH1-PKN1 interaction surface.The figure illustrates the crystal structure of the LRR of SspH1 in complex with the HR1b of PKN1 (cyan) (PDB ID 4NKG). Protein surface and cartoon representation of SspH1 are shown in gray and orange, respectively. H392 of SspH1 is shown in magenta. The contact interface between LRR and NEL is indicated by a dashed oval. The molecular graphics were prepared using PyMOL [76].
Mentions: Salmonella SspH1, another NEL family member, induces protein kinase N1 (PKN1) degradation in a ubiquitin- and proteasome-dependent manner [36]. PKN1 interacts with androgen receptor (AR), functions as a transcriptional coactivator, and regulates a wide range of cellular processes including cytoskeletal regulation, tumorigenesis, and transcription [74,75]. In 293T cells, expression of wild-type SspH1, but not E3 ligase-dead or SspH1-PKN1 interface mutants, suppresses the AR-responsive element [37]. Degradation of PKN1 by SspH1 attenuates the AR response (Figure 2A).

Bottom Line: Modulation of the host ubiquitin system by bacterial effector proteins inhibits innate immune responses and hijacks central signaling pathways.Bacterial effectors mimic enzymes of the host ubiquitin system, but may or may not be structurally similar to the mammalian enzymes.Other effectors bind and modify components of the host ubiquitin system, and some are themselves subject to ubiquitination.

View Article: PubMed Central - PubMed

Affiliation: Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai 4-6-1, Minato-ku 4-6-1, Tokyo 108-8639, Japan. minsoo@ims.u-tokyo.ac.jp.

ABSTRACT
Protein ubiquitination plays indispensable roles in the regulation of cell homeostasis and pathogenesis of neoplastic, infectious, and neurodegenerative diseases. Given the importance of this modification, it is to be expected that several pathogenic bacteria have developed the ability to utilize the host ubiquitin system for their own benefit. Modulation of the host ubiquitin system by bacterial effector proteins inhibits innate immune responses and hijacks central signaling pathways. Bacterial effectors mimic enzymes of the host ubiquitin system, but may or may not be structurally similar to the mammalian enzymes. Other effectors bind and modify components of the host ubiquitin system, and some are themselves subject to ubiquitination. This review will describe recent findings, based on structural analyses, regarding how pathogens use post-translational modifications of proteins to establish an infection.

No MeSH data available.


Related in: MedlinePlus