Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice

Yuan, Siqi; Yao, Fang; Tang, Mengling; Hu, Zhiqiang; Rao, C. S.; Chen, Jiangao; Xia, Yupei; Zhang, Meijuan; Yan, Jingmin; Tang, Bin; He, Xiaoyi; Xie, Jianping; Mao, Xuhu; Li, Qian

doi:10.1186/s12866-021-02199-x

Cited by 3 publications

(2 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid usually produced endogenously in the human liver from taurine conjugated with ursodeoxycholic acid (UDCA). TUDCA has been used in the clinical treatment of hepatobiliary disorders and is a well-recognized inhibitor of ER stress(Yuan et al 2021 ). Recent clinical trials have used TUDCA as an ER stress inhibitor in the treatment of diabetes, cardiovascular disease, and human hypertension.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Yuan,

She,

Jiang

et al. 2024

Mol Med

Self Cite

View full text Add to dashboard Cite

The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways—inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER’s protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions.

show abstract

Section: Therapeutic Strategiesmentioning

confidence: 99%

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Yuan,

She,

Jiang

et al. 2024

Mol Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Burkholderia pseudomallei is responsible for up to 40% sepsis-related mortality. TUDCA promoted B. pseudomallei clearance by inhibiting endoplasmic reticulum (ER) stress-induced apoptosis [56]. Recently, conjugated bile acids have been found to increase the integrity of the gut barrier [29,57].…”

Section: Gut Origin Of Sepsismentioning

confidence: 99%

Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases

Shi

Jin

Huang

2023

Cells

View full text Add to dashboard Cite

The intestinal barrier is a precisely regulated semi-permeable physiological structure that absorbs nutrients and protects the internal environment from infiltration of pathological molecules and microorganisms. Bile acids are small molecules synthesized from cholesterol in the liver, secreted into the duodenum, and transformed to secondary or tertiary bile acids by the gut microbiota. Bile acids interact with bile acid receptors (BARs) or gut microbiota, which plays a key role in maintaining the homeostasis of the intestinal barrier. In this review, we summarize and discuss the recent studies on bile acid disorder associated with intestinal barrier dysfunction and related diseases. We focus on the roles of bile acids, BARs, and gut microbiota in triggering intestinal barrier dysfunction. Insights for the future prevention and treatment of intestinal barrier dysfunction and related diseases are provided.

show abstract

Burkholderia pseudomallei BopE suppresses the Rab32-dependent defense pathway to promote its intracellular replication and virulence

Rao,

Zhang,

Qiao

et al. 2024

mSphere

View full text Add to dashboard Cite

Melioidosis is a serious infectious disease caused by the Gram-negative bacterium Burkholderia pseudomallei . Recently, Rab32-dependent immune vesicles emerge as a critical defense pathway to restrict the intracellular B. pseudomallei . However, B. pseudomallei can evade host immune vesicles and survive in the cytoplasm, although this mechanism is not well understood. In this study, we found Rab32-dependent vesicles could effectively combat B. pseudomallei infection, but not all intracellular B. pseudomallei were encapsulated in Rab32-positive vesicles. To explore how B. pseudomallei counteracted the Rab32-dependent defense pathway, transcriptomic profiling of B. pseudomallei was performed to characterize the response dynamics during infection. We found that the type III secretion system of B. pseudomallei was activated, and a variety of effector proteins were highly upregulated. Among them, BopE, BprD, and BipC were shown to interact with Rab32. Interestingly, BopE directly interacts with host Rab32, potentially suppressing Rab32 function by interfering with nucleotide exchange, which in turn restricts the recruitment of Rab32 to bacterial-containing vesicles. Knocking out of BopE can increase the proportion of Rab32-positive vesicles, suppressing the intracellular replication and virulence of B. pseudomallei . Collectively, our findings have demonstrated that BopE may be an important effector for B. pseudomallei to evade from the Rab32-dependent killing vesicles into the cytosol for survival and replication. Therefore, a deeper understanding of the interaction between BopE and the host Rab32-dependent restriction pathway may provide an effective therapeutic strategy for the elimination of intracellular B. pseudomallei . IMPORTANCE B. pseudomallei is facultative intracellular bacterium that has evolved numerous strategies to evade host immune vesicles and survive in the cytoplasm. Rab32-dependent vesicles are one of these immune vesicles, but the mechanism by which B. pseudomallei escape Rab32-dependent vesicles remains elusive. Here, we find B. pseudomallei infection leading the activation of the type III secretion system (T3SS-3) and increasing the expression of various effectors. Specifically, we identify that BopE, an effector secreted by T3SS-3, triggers vesicle escape to promote B. pseudomallei pathogenicity and survival. Mechanistically, BopE suppresses the activation of Rab32 by interfering with nucleotide exchange, ultimately triggering vesicle escape and intracellular survival. We also find knocking out the bopE gene can increase the proportion of Rab32-positive vesicles that trap B. pseudomallei , dampening the survival of B. pseudomallei both in vitro and in vivo . Taken together, our findings provide insights into the molecular mechanisms of pathogen effector-induced vesicle escape, indicating a potential melioidosis treatment via blocking B. pseudomallei BopE-host Rab32 interaction.

show abstract

Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice

Cited by 3 publications

References 46 publications

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases

Burkholderia pseudomallei BopE suppresses the Rab32-dependent defense pathway to promote its intracellular replication and virulence

Contact Info

Product

Resources

About