Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection

Mukherjee, Madhuchhanda; Ball, Writoban Basu; Das, Pritha

doi:10.1016/j.biocel.2014.08.019

Cited by 17 publications

(18 citation statements)

References 40 publications

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“…1D, decreased SREBP2 expression was detected in the normal Het-1A cells. The N-terminus of SREBP2 [SREBP2(N)] serves as a transcriptional factor following cleavage (16). Therefore, the expression levels of the active form of SREBP2 in ESCC tissues and cell lines were additionally detected.…”

Section: Resultsmentioning

confidence: 99%

SREBP2 is upregulated in esophageal squamous cell carcinoma and co‑operates with c‑Myc to regulate HMGCR expression

Zhong

Fan

et al. 2019

Mol Med Report

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Dysregulations of the mevalonate pathway (MVA) have been previously identified. Our previous study demonstrated that 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the MVA pathway, was upregulated in esophageal squamous cell carcinoma (ESCC) and statin-inhibited ESCC tumorigenesis. However, the underlying mechanism of HMGCR regulation in ESCC remains unknown. In the present study, western blotting and immunohistochemistry analysis demonstrated that sterol regulatory element-binding protein 2 (SREBP2), the master regulator for HMGCR, was upregulated in ESCC clinical samples. Overexpression of SREBP2 expression in ESCC cell lines promoted the growth, migration and colony formation of cancer cells in the MTT, Boyden chamber and soft agar assays, respectively, which was inhibited by lovastatin. Downregulation of SREBP2 expression in ESCC cell lines inhibited the viability, and migration and colony formation abilities of cancer cells. Assessment of the molecular mechanism demonstrated that SREBP2 interacted with c-Myc and cooperated with c-Myc to activate HMGCR expression. Collectively, the present study identified SREBP2 as an oncogene associated with the tumorigenesis of ESCC and further demonstrated the therapeutic effects of statins in ESCC.

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Section: Resultsmentioning

confidence: 99%

SREBP2 is upregulated in esophageal squamous cell carcinoma and co‑operates with c‑Myc to regulate HMGCR expression

Zhong

Fan

et al. 2019

Mol Med Report

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“…As mtROS play key roles in the maintenance of cellular homeostasis, such as autophagy (16,17), additional studies are warranted to elucidate the roles of mtROS in the activation of xenophagy in the context of the innate immune defense. Although relatively uncharacterized in the function of mtROS in terms of antiparasitic defense, mtROS contributed to upregulating the intracellular clearance of Leishmania donovani, an intracellular parasite (18,19).…”

Section: Mtros In Antibacterial and Antiparasitic Defensementioning

confidence: 99%

“…Early studies showed that the intracellular parasite Leishmania donovani targets and stabilizes host transcriptional factor SREBP2 to regulate macrophage cholesterol and inhibit microbicidal mtROS production, thereby favoring parasite persistence (18). In another study, L. donovani infection induced the upregulation of uncoupling protein 2 (UCP2) to inhibit mtROS generation, thereby attenuating host Th1-biased immune response and parasitic clearance (19).…”

Section: Pathogens Modulate Mtros To Promote Pathogenesis and Virulencementioning

confidence: 99%

Mitochondrial Reactive Oxygen Species: Double-Edged Weapon in Host Defense and Pathological Inflammation During Infection

Silwal

Kim

et al. 2020

Front. Immunol.

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Mitochondria are inevitable sources for the generation of mitochondrial reactive oxygen species (mtROS) due to their fundamental roles in respiration. mtROS were reported to be bactericidal weapons with an innate effector function during infection. However, the controlled generation of mtROS is vital for the induction of efficient immune responses because excessive production of mtROS with mitochondrial damage leads to sustained inflammation, resulting in pathological outcomes such as sepsis. Here, we discuss the beneficial and detrimental roles of mtROS in the innate immune system during bacterial, viral, and fungal infections. Recent evidence suggests that several pathogens have evolved multiple strategies to modulate mtROS for their own benefit. We are just beginning to understand the mechanisms by which mtROS generation is regulated and how mtROS affect protective and pathological responses during infection. Several agents/small molecules that prevent the uncontrolled production of mtROS are known to be beneficial in the maintenance of tissue homeostasis during sepsis. mtROS-targeted approaches need to be incorporated into preventive and therapeutic strategies against a variety of infections.

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“…The protein expression level of HMGCR is tightly controlled at multiple levels. Sterol regulatory element-binding protein 2 is a key modulator of HMGCR via regulation of its transcription (9). On the other hand, ubiquitin fusion degradation (UFD) and autocrine motility factor receptor (GP78) promoted the degradation of the HMGCR protein (10).…”

Section: Introductionmentioning

confidence: 99%

HSP90 interacts with HMGCR and promotes the progression of hepatocellular carcinoma

Xue

Zhang

et al. 2018

Mol Med Report

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Heat shock protein 90 (HSP90) has been reported to promote the growth and inhibit apoptosis of hepatocellular carcinoma (HCC) cells. However, the underlying mechanisms are not fully understood. Immunostaining of the tissue array demonstrated that HSP90 was upregulated in HCC clinical samples and was associated with clinical features. HSP90 interacted with 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of mevalonate pathway, in the immunoprecipitation assay and regulated its protein expression level by inhibiting protein degradation. In addition, lovastatin, an inhibitor of HMGCR, impaired the oncogenic functions of HSP90 in the cell growth, migration and colony formation assays. Taken together, this study demonstrated that HSP90 promoted the progression of HCC by positively regulating the mevalonate pathway and indicated that HSP90 may be a promising therapeutic target.

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Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection

Cited by 17 publications

References 40 publications

SREBP2 is upregulated in esophageal squamous cell carcinoma and co‑operates with c‑Myc to regulate HMGCR expression

SREBP2 is upregulated in esophageal squamous cell carcinoma and co‑operates with c‑Myc to regulate HMGCR expression

Mitochondrial Reactive Oxygen Species: Double-Edged Weapon in Host Defense and Pathological Inflammation During Infection

HSP90 interacts with HMGCR and promotes the progression of hepatocellular carcinoma

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