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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

Bacterial effectors manipulate the host ubiquitin-proteasome system (UPS). After translocation into host cells, several effectors (black squares) target the host’s UPS. (A) Some effectors are ubiquitinated and then either degraded by the proteasome or functionally modified; (B) Some effectors, such as ubiquitin ligases (E3s), act as UPS enzymes; (C) Other effectors inhibit specific UPS steps. Bacterial effectors can mimic or hijack the host’s UPS to modulate host cell responses such as immune responses, cell death, and clearance of bacteria.
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cells-03-00848-f001: Bacterial effectors manipulate the host ubiquitin-proteasome system (UPS). After translocation into host cells, several effectors (black squares) target the host’s UPS. (A) Some effectors are ubiquitinated and then either degraded by the proteasome or functionally modified; (B) Some effectors, such as ubiquitin ligases (E3s), act as UPS enzymes; (C) Other effectors inhibit specific UPS steps. Bacterial effectors can mimic or hijack the host’s UPS to modulate host cell responses such as immune responses, cell death, and clearance of bacteria.

Mentions: These effectors are classified into three types (Figure 1): (A) effectors that are targeted by the host ubiquitin ligases and are quickly inactivated by degradation or modified by ubiquitination, thereby diversifying effector function; (B) effectors with UPS enzyme activity, such as E3 ubiquitin ligase and DUB activity; and (C) effectors that modulate steps of the UPS. Examples of each type follow: (A) The Salmonella effectors SopE and SptP are degraded sequentially by ubiquitination to regulate bacterial invasion [61]. Yersinia YopE is ubiquitinated, and degradation of YopE contributes to the spread of bacteria in host tissues [62,63]. However, the host or bacterial E3 proteins that ubiquitinate these effectors are still unknown. Ubiquitination of Salmonella SopB diversifies its function by altering its subcellular localization [64,65]. (B) Salmonella SseL exhibits DUB activity in vitro and is required for Salmonella infection in mice [66]. Salmonella SopA and EHEC NleL are structurally similar to mammalian HECT E3 ligases, although their substrates are unknown [22,23,24,25]. Crystallographic analysis has revealed that the Pseudomonas syringae effector AvrPtoB, which suppresses immune responses triggered by pathogen-associated molecular patterns, is a structural mimic of the RING family of E3 ligases [67]. AvrPtoB binds to several host kinases such as Fen kinase and BRI1-associated kinase1 (BAK1), which are important for plant immunity [68], resulting in their ubiquitination and degradation [29,30,31,32]. (C) The EPEC effector NleE methylates TAB2 and TAB3, an activator of the NFκB pathway [69], and this modification blocks host NFκB signaling [70]. The Shigella effector IpaB binds to Mad2L2, an APC inhibitor, to inhibit host cell-cycle progression [71].


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)

Bacterial effectors manipulate the host ubiquitin-proteasome system (UPS). After translocation into host cells, several effectors (black squares) target the host’s UPS. (A) Some effectors are ubiquitinated and then either degraded by the proteasome or functionally modified; (B) Some effectors, such as ubiquitin ligases (E3s), act as UPS enzymes; (C) Other effectors inhibit specific UPS steps. Bacterial effectors can mimic or hijack the host’s UPS to modulate host cell responses such as immune responses, cell death, and clearance of bacteria.
© Copyright Policy
Related In: Results  -  Collection

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

cells-03-00848-f001: Bacterial effectors manipulate the host ubiquitin-proteasome system (UPS). After translocation into host cells, several effectors (black squares) target the host’s UPS. (A) Some effectors are ubiquitinated and then either degraded by the proteasome or functionally modified; (B) Some effectors, such as ubiquitin ligases (E3s), act as UPS enzymes; (C) Other effectors inhibit specific UPS steps. Bacterial effectors can mimic or hijack the host’s UPS to modulate host cell responses such as immune responses, cell death, and clearance of bacteria.
Mentions: These effectors are classified into three types (Figure 1): (A) effectors that are targeted by the host ubiquitin ligases and are quickly inactivated by degradation or modified by ubiquitination, thereby diversifying effector function; (B) effectors with UPS enzyme activity, such as E3 ubiquitin ligase and DUB activity; and (C) effectors that modulate steps of the UPS. Examples of each type follow: (A) The Salmonella effectors SopE and SptP are degraded sequentially by ubiquitination to regulate bacterial invasion [61]. Yersinia YopE is ubiquitinated, and degradation of YopE contributes to the spread of bacteria in host tissues [62,63]. However, the host or bacterial E3 proteins that ubiquitinate these effectors are still unknown. Ubiquitination of Salmonella SopB diversifies its function by altering its subcellular localization [64,65]. (B) Salmonella SseL exhibits DUB activity in vitro and is required for Salmonella infection in mice [66]. Salmonella SopA and EHEC NleL are structurally similar to mammalian HECT E3 ligases, although their substrates are unknown [22,23,24,25]. Crystallographic analysis has revealed that the Pseudomonas syringae effector AvrPtoB, which suppresses immune responses triggered by pathogen-associated molecular patterns, is a structural mimic of the RING family of E3 ligases [67]. AvrPtoB binds to several host kinases such as Fen kinase and BRI1-associated kinase1 (BAK1), which are important for plant immunity [68], resulting in their ubiquitination and degradation [29,30,31,32]. (C) The EPEC effector NleE methylates TAB2 and TAB3, an activator of the NFκB pathway [69], and this modification blocks host NFκB signaling [70]. The Shigella effector IpaB binds to Mad2L2, an APC inhibitor, to inhibit host cell-cycle progression [71].

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