An infection-induced RhoB-Beclin 1-Hsp90 complex enhances clearance of uropathogenic Escherichia coli

Miao, Chunhui; Yu, Mingyu; Pei, Geng; Ma, Zhenyi; Zhang, Lisong; Yang, Jianming; Lv, Junqiang; Zhang, Zhisong; Keller, Evan T.; Yao, Zhi; Wang, Quan

doi:10.1038/s41467-021-22726-8

Cited by 17 publications

(11 citation statements)

References 44 publications

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“…The Pearson's co-localization coefficients of intracellular XL1 blue, ST999, and ST95 with LAMP1 were 0.11 (± 0.02; n = 372 cells), 0.37 (± 0.05; n = 1,689), and 0.57 (± 0.02; n = 1,859), respectively (Figure 5D). Moreover, we found that ST999 and ST95 increased lipidated LC3-II levels (Figure 5F), as has been previously reported for UPEC infected epithelial cells [68].…”

Section: St999 and St95 Survive In Epithelial Cellssupporting

confidence: 89%

Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells

Dabral

Ghosh

Niwa

et al. 2022

Preprint

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By far most urinary tract infections are caused by genetically diverse uropathogenic Escherichia coli (UPEC). Knowledge of the virulence mechanisms of UPEC is critical for drug development, but most studies focus on only a single strain of UPEC. In this study, we compared the virulence mechanisms of four antibiotic-resistant and highly pathogenic UPEC isolates in human blood monocyte-derived macrophages and a bladder epithelial cell (BEC) line: ST999, ST131, ST1981 and ST95. We found that while non-pathogenic E. coli strains are efficiently killed by macrophages in bactericidal single membrane vacuoles, the UPEC strains survive within double-membrane vacuoles. On side-by-side comparison, we found that whereas ST999 only carries Fe3+ importers, ST95 carries both Fe2+ and Fe3+ importers and the toxins hemolysin and colibactin. Moreover, we found that ST999 grows in the Fe3+ rich vacuoles of BECs and macrophages with concomitant increased expression of haem receptor chuA and the hydrogen peroxide sensor oxyR. In contrast, ST95 produces toxins in iron-depleted conditions similar to that of the urinary tract. Whereas ST95 also persist in the iron rich vacuoles of BECs, it produces colibactin in response to low Fe3+ contributing to macrophage death. Thus, iron regulates the contrasting toxicities of UPEC strains in macrophages and bladder epithelial cells due to low and high labile iron concentrations, respectively.

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Section: St999 and St95 Survive In Epithelial Cellssupporting

confidence: 89%

Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells

Dabral

Ghosh

Niwa

et al. 2022

Preprint

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“…We further studied how RhoB expression altered intestinal microbiome. As we found that RhoB promoted autophagic flux [ 19 ], and it is also reported that autophagy leads to alteration of the microbiota composition [ 24 , 25 ], we examined whether alteration of the microbiome resulted from RhoB-mediated autophagy. WT and RhoB −/− mice were treated with rapamycin (widely used to induce autophagy in mice [ 26 ]) before DSS challenge.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous study identified a vital role of RhoB in promoting autophagy [ 19 ]. Therefore, we speculate that decreased RhoB may shape microbiota by regulating autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…RhoB, a member of the small Rho GTPase family, is rapidly upregulated by stress-induced signaling events including genotoxic stress, lipopolysaccharide (LPS), inflammatory cytokines, growth factors, and toxins [ 16 ]. RhoB regulates multiple cellular processes, including vesicular transport, apoptosis, DNA repair, angiogenesis, proliferation, migration, and invasion [ 17 , 18 ], and we recently reported that RhoB promoted autophagic flux to enhance clearance of uropathogenic Escherichia coli [ 19 ]. However, the role of RhoB in colitis remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

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RhoB affects colitis through modulating cell signaling and intestinal microbiome

et al. 2022

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Background The pathogenesis of inflammatory bowel diseases (IBD) is multifactorial, and diagnostic and treatment strategies for IBD remain to be developed. RhoB regulates multiple cell functions; however, its role in colitis is unexplored. Results Here, we found RhoB was dramatically increased in colon tissues of ulcerative colitis (UC) patients and mice with DSS-induced colitis. Compared with wild type mice, RhoB+/− and RhoB−/− mice developed milder DSS-induced colitis and increased goblet cell numbers and IEC proliferation. Decreased RhoB promoted goblet cell differentiation and epithelial regeneration through inhibiting Wnt signaling pathway and activating p38 MAPK signaling pathway. Moreover, increased SCFA-producing bacteria and SCFA concentrations were detected in intestinal microbiome of both RhoB+/− and RhoB−/− mice and upregulated SCFA receptor expression was also observed. Conclusions Taken together, a higher level of RhoB is associated with UC, which also contributes to UC development through modulating cell signaling and altering intestinal bacterial composition and metabolites. These observations suggest that RhoB has potential as a biomarker and a treatment target for UC.

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“…Previous studies reported that the NF-κB signaling pathway was activated in RIRI, leading to aggravation of tubular injury and exacerbation of inflammatory response, while its inhibition improves renal function ( 50 , 51 ). Besides, Btg2 can be aberrantly stimulated by activation of NF-κB signaling as a response to oxidative stress ( 52 ), and Rhob is transiently upregulated by cell exposure to inflammatory cytokines, which may be dependent on the NF-κB pathway ( 53 ). Combined with our results, we infer that Btg2 and Rhob function through the NF-κB signaling pathway during RIRI.…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Prognostic Genes Associated With Ischemia–Reperfusion Injury in Renal Transplantation

et al. 2021

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BackgroundIschemia–reperfusion injury (IRI) remains an inevitable and major challenge in renal transplantation. The current study aims to obtain deep insights into underlying mechanisms and seek prognostic genes as potential therapeutic targets for renal IRI (RIRI).MethodsAfter systematically screening the Gene Expression Omnibus (GEO) database, we collected gene expression profiles of over 1,000 specimens from 11 independent cohorts. Differentially expressed genes (DEGs) were identified by comparing allograft kidney biopsies taken before and after reperfusion in the discovery cohort and further validated in another two independent transplant cohorts. Then, graft survival analysis and immune cell analysis of DEGs were performed in another independent renal transplant cohort with long-term follow-ups to further screen out prognostic genes. Cell type and time course analyses were performed for investigating the expression pattern of prognostic genes in more dimensions utilizing a mouse RIRI model. Finally, two novel genes firstly identified in RIRI were verified in the mouse model and comprehensively analyzed to investigate potential mechanisms.ResultsTwenty DEGs upregulated in the process of RIRI throughout different donor types (living donors, cardiac and brain death donors) were successfully identified and validated. Among them, upregulation of 10 genes was associated with poor long-term allograft outcomes and exhibited strong correlations with prognostic immune cells, like macrophages. Furthermore, certain genes were found to be only differentially expressed in specific cell types and remained with high expression levels even months after RIRI in the mouse model, which processed the potential to serve as therapeutic targets. Importantly, two newly identified genes in RIRI, Btg2 and Rhob, were successfully confirmed in the mouse model and found to have strong connections with NF-κB signaling.ConclusionsWe successfully identified and validated 10 IRI-associated prognostic genes in renal transplantation across different donor types, and two novel genes with crucial roles in RIRI were recognized for the first time. Our findings offered promising potential therapeutic targets for RIRI in renal transplantation.

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An infection-induced RhoB-Beclin 1-Hsp90 complex enhances clearance of uropathogenic Escherichia coli

Cited by 17 publications

References 44 publications

Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells

Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells

RhoB affects colitis through modulating cell signaling and intestinal microbiome

Integrated Analysis of Prognostic Genes Associated With Ischemia–Reperfusion Injury in Renal Transplantation

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