SUMO4 and its role in type 1 diabetes pathogenesis

Wang, Cong Yi; She, Jin Xiong

doi:10.1002/dmrr.797

Cited by 60 publications

(49 citation statements)

References 107 publications

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“…The SUMO2/3 proteins are often conjugated to proteins in response to a signaling or stress stimulus (17,43). SUMO4 was recently identified, and polymorphisms of this isoform have been linked to several disease states (44,45); however, it remains ambiguous whether SUMO4 is a direct protein modifier or a pseudogene (46,47).…”

Section: Resultsmentioning

confidence: 99%

Ehrlichia chaffeensis Exploits Host SUMOylation Pathways To Mediate Effector-Host Interactions and Promote Intracellular Survival

2014

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Ehrlichia chaffeensis is an obligately intracellular Gram-negative bacterium that selectively infects mononuclear phagocytes. We recently reported that E. chaffeensis utilizes a type 1 secretion (T1S) system to export tandem repeat protein (TRP) effectors and demonstrated that these effectors interact with a functionally diverse array of host proteins. By way of these interactions, TRP effectors modulate host cell functions; however, the molecular basis of these interactions and their roles in ehrlichial pathobiology are not well defined. In this study, we describe the first bacterial protein posttranslational modification (PTM) by the small ubiquitin-like modifier (SUMO). The E. chaffeensis T1S effector TRP120 is conjugated to SUMO at a carboxy-terminal canonical consensus SUMO conjugation motif in vitro and in human cells. In human cells, TRP120 was selectively conjugated with SUMO2/3 isoforms. Disruption of TRP120 SUMOylation perturbed interactions with known host proteins, through predicted SUMO interaction motif-dependent and -independent mechanisms. E. chaffeensis infection did not result in dramatic changes in the global host SUMOylated protein profile, but a robust colocalization of predominately SUMO1 with ehrlichial inclusions was observed. Inhibiting the SUMO pathway with a small-molecule inhibitor had a significant impact on E. chaffeensis replication and recruitment of the TRP120-interacting protein polycomb group ring finger protein 5 (PCGF5) to the inclusion, indicating that the SUMO pathway is critical for intracellular survival. This study reveals the novel exploitation of the SUMO pathway by Ehrlichia, which facilitates effector-eukaryote interactions necessary to usurp the host and create a permissive intracellular niche. Ehrlichia chaffeensis, the etiologic agent of the life-threatening tick-borne zoonosis human monocytotropic ehrlichiosis (HME), is an obligately intracellular Gram-negative bacterium that selectively infects mononuclear phagocytes and replicates in cytoplasmic vacuoles resembling endosomes (1-3). The mechanisms through which E. chaffeensis directs internalization, establishes intracellular infection, and avoids innate and adaptive host defenses are not well understood. However, we identified a group of type 1 secretion (T1S) system ehrlichial tandem repeat protein (TRP) effectors, similar to the repeats-in-toxin family of exoproteins, that are involved in novel molecular interactions with a large group of functionally diverse host cell proteins and host cell DNA (4-9).E. chaffeensis TRP120 is a major immunoreactive protein that is found on the surfaces of infectious dense-cored ehrlichiae and is expressed in both arthropod and mammalian cells (10, 11). A single major linear epitope (22 amino acids) in the tandem repeat region of TRP120 has been identified that elicits protective antibodies (12). Following T1S, TRP120 crosses the ehrlichial vacuole membrane through an unknown mechanism, similar to the Chlamydia trachomatis protein effector CPAF (13), and is present in the host...

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Section: Resultsmentioning

confidence: 99%

Ehrlichia chaffeensis Exploits Host SUMOylation Pathways To Mediate Effector-Host Interactions and Promote Intracellular Survival

2014

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“…The differences of diabetes incidence between groups were determined using the log-rank (Mantel-Cox) test. 2 test was used to determine the difference for insulitis severity at each time point. Comparisons between groups for flow cytometry, cytokine production, and intracellular cytokine expression were accomplished by one-way ANOVA using SPS 11.5 for Windows.…”

Section: Conclusion-extracellularmentioning

confidence: 99%

“…Interestingly, the number of CD8 ϩ interferon-␥ ϩ (Tc1) T-cells was increased in the PLNs and spleen after blockade of HMGB1, which could be associated with retarded migration of activated autoreactive T-cells into the pancreatic islets. T ype 1 diabetes is an autoimmune disease characterized by T-cell-mediated destruction of the insulin-secreting ␤-cells (1)(2)(3). It is believed that environmental risk factors interact with genetic factors to trigger the development of autoimmunity.…”

mentioning

confidence: 99%

Extracellular High-Mobility Group Box 1 Acts as an Innate Immune Mediator to Enhance Autoimmune Progression and Diabetes Onset in NOD Mice

et al. 2008

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OBJECTIVE— The implication of innate immunity in type 1 diabetes development has long been proposed. High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was recently recognized to be a potent innate inflammatory mediator when released extracellularly. We sought to test the hypothesis that HMGB1 acts as an innate immune mediator implicated in type 1 diabetes pathogenesis. RESEARCH DESIGN AND METHODS— Eight- and 12-week-old NOD mice were treated with an HMGB1 neutralizing antibody once a week until 25 weeks of age and monitored for insulitis progression and diabetes onset. The underlying mechanisms of HMGB1 regulation of autoimmune response were further explored. RESULTS— During autoimmunity, HMGB1 can be passively released from damaged pancreatic β-cells and actively secreted by islet infiltrated immune cells. Extracellular HMGB1 is potent in inducing NOD dendritic cell maturation and stimulating macrophage activation. Blockade of HMGB1 significantly inhibited insulitis progression and diabetes development in both 8- and 12-week-old NOD mice. HMGB1 antibody treatment decreased the number and maturation of pancreatic lymph node (PLN) CD11c ++ CD11b + dendritic cells, a subset of dendritic cells probably associated with autoantigen presentation to naïve T-cells, but increased the number for PLN CD4 + Foxp3 + regulatory T-cells. Blockade of HMGB1 also decreased splenic dendritic cell allo-stimulatory capability associated with increased tolergenic CD11c + CD8a + dendritic cells. Interestingly, the number of CD8 + interferon-γ + (Tc1) T-cells was increased in the PLNs and spleen after blockade of HMGB1, which could be associated with retarded migration of activated autoreactive T-cells into the pancreatic islets. CONCLUSIONS— Extracellular HMGB1 functions as a potent innate immune mediator contributing to insulitis progression and diabetes onset.

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“…However, further studies revealed that results may vary at the level of individual targets, depending on stress intensity or duration (Dohmen 2004;Saitoh and Hinchey 2000;Tempe et al 2008). Human SUMO-1 has been reported to modify Ran GTPase activating protein 1 (RanGAP1) (Matunis et al 1996) and regulate the promyelocytic leukemia (PML)/p53 tumor suppressor network (Fogal et al 2000), whereas SUMO-4 is associated with stress response and type 1 diabetes (Guo et al 2004;Wang and She 2008). Furthermore, SUMO-1 and SUMO-2/3 are ubiquitously expressed, while SUMO-4 seems to be expressed primarily in the lymph node and spleen (Guo et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Biochemical characterization of the small ubiquitin-like modifiers of Chlamydomonas reinhardtii

Shin

Liu

Tsai

et al. 2010

Planta

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Dynamic modification of target proteins by small ubiquitin-like modifier (SUMO) is known to modulate many important cellular processes and is required for cell viability and development in all eukaryotes. However, understanding of SUMO systems in plants, especially in unicellular green algae, remains elusive. In this study, Chlamydomonas reinhardtii CrSUMO96, CrSUMO97 and CrSUMO148 were characterized. We show that the formation of polymeric CrSUMO96 and CrSUMO97 chains can be catalyzed either by the human SAE1/SAE2 and Ubc9 SUMOylation system in vitro or by an Escherichia coli chimeric SUMOylation system in vivo. An exposed C-terminal di-glycine motif of CrSUMO96 or CrSUMO97 is essential for functional SUMOylation. The human SUMO-specific protease, SENP1, demonstrates more processing activity for CrSUMO97 than for CrSUMO96. The CrSUMO148 precursor notably has four repeated di-glycine motifs at the C-terminus. This unique feature is not found in other known SUMO proteins. Interestingly, only 83-residual CrSUMO148(1-83) with the first di-glycine motif can form SAE1/SAE2-SUMO complex and further form polymeric chains with the help of Ubc9. More surprisingly, CrSUMO148 precursor is digested by SENP1, solely at the peptide bond after the first di-glycine motif although there are four theoretically identical processing sites in the primary sequence. This process directly generates 83-residual CrSUMO148(1-83) mature protein, which is exactly the form suitable for activation and conjugation. We also show that SENP1 displays similar isopeptidase activity in the deconjugation of polymeric CrSUMO96, CrSUMO97 or CrSUMO148 chains, revealing that the catalytic mechanisms of processing and deconjugation of CrSUMOs by SENP1 may differ.

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SUMO4 and its role in type 1 diabetes pathogenesis

Cited by 60 publications

References 107 publications

Ehrlichia chaffeensis Exploits Host SUMOylation Pathways To Mediate Effector-Host Interactions and Promote Intracellular Survival

Ehrlichia chaffeensis Exploits Host SUMOylation Pathways To Mediate Effector-Host Interactions and Promote Intracellular Survival

Extracellular High-Mobility Group Box 1 Acts as an Innate Immune Mediator to Enhance Autoimmune Progression and Diabetes Onset in NOD Mice

Biochemical characterization of the small ubiquitin-like modifiers of Chlamydomonas reinhardtii

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