In vitro studies on the role of the peripheral-type benzodiazepine receptor in steroidogenesis

Culty, Martine; Li, H; Boujrad, Noureddine; Amri, Hakima; Vidić, Branislav; Bernassau, Jean‐Marie; Reversat, Jean-Louis; Papadopoulos, Vassilios

doi:10.1016/s0960-0760(99)00056-4

Cited by 108 publications

(56 citation statements)

References 42 publications

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“…4A), and there is significant variation in the topology of proteins with ␣-helical transmembrane domains as well as their mechanism of integration into the membrane. For example, the ubiquitin ligase MARCH5 and translocator protein (TSPO), which comprise four and five helical transmembrane domains, respectively (36)(37)(38)(39), require the Tom70 receptor for integration into the outer membrane (40). To the contrary, another multispanning membrane protein, Ugo1, appears to rely on the lipid composition of the outer membrane for its biogenesis (41).…”

Section: Discussionmentioning

confidence: 99%

A Farnesylated Coxiella burnetii Effector Forms a Multimeric Complex at the Mitochondrial Outer Membrane during Infection

et al. 2017

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Coxiella burnetii, the causative agent of Q fever, establishes a unique lysosome-derived intracellular niche termed the Coxiella-containing vacuole (CCV). The Dot/Icm-type IVB secretion system is essential for the biogenesis of the CCV and the intracellular replication of Coxiella. Effector proteins, translocated into the host cell through this apparatus, act to modulate host trafficking and signaling processes to facilitate CCV development. Here we investigated the role of CBU0077, a conserved Coxiella effector that had previously been observed to localize to lysosomal membranes. CBU0077 was dispensable for the intracellular replication of Coxiella in HeLa and THP-1 cells and did not appear to participate in CCV biogenesis. Intriguingly, native and epitope-tagged CBU0077 produced by Coxiella displayed specific punctate localization at host cell mitochondria. As such, we designated CBU0077 MceA (mitochondrial Coxiella effector protein A). Analysis of ectopically expressed MceA truncations revealed that the capacity to traffic to mitochondria is encoded within the first 84 amino acids of this protein. MceA is farnesylated by the host cell; however, this does not impact mitochondrial localization. Examination of mitochondria isolated from infected cells revealed that MceA is specifically integrated into the mitochondrial outer membrane and forms a complex of approximately 120 kDa. Engineering Coxiella to express either MceA tagged with 3ϫFLAG or MceA tagged with 2ϫhemagglutinin allowed us to perform immunoprecipitation experiments that showed that MceA forms a homo-oligomeric species at the mitochondrial outer membrane during infection. This research reveals that mitochondria are a bona fide target of Coxiella effectors and MceA is a complex-forming effector at the mitochondrial outer membrane during Coxiella infection.KEYWORDS Coxiella burnetii, bacterial effector, mitochondria, prenylation, hostpathogen interactions C oxiella burnetii is the causative agent of human Q fever, a zoonotic infection with a worldwide distribution. The extremely low infectious dose, the ease of aerosol dissemination, and the environmental stability of this pathogen all contribute to Coxiella being classified as a category B select agent by the U.S. Centers for Disease Control and Prevention (1, 2).During human infection, inhaled Coxiella bacteria predominantly infect alveolar macrophages, where they develop a unique intracellular replicative niche termed the Coxiella-containing vacuole (CCV). Internalized bacteria are trafficked through the endocytic pathway until they reach the acidic and hydrolytic confines of the lysosome.

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Section: Discussionmentioning

confidence: 99%

A Farnesylated Coxiella burnetii Effector Forms a Multimeric Complex at the Mitochondrial Outer Membrane during Infection

et al. 2017

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“…Hydropathy profile and experimental analysis have suggested that TSPO possesses a five-transmembrane structure (32,33), findings recently supported by electron cryomicroscopy of a bacterial homolog (34). Deletion of the C terminus of recombinant mammalian TSPO, which contains the CRAC motif, severely reduced cholesterol uptake when expressed in Escherichia coli, although PK 11195 binding was retained (25).…”

mentioning

confidence: 90%

Novel Androstenetriol Interacts with the Mitochondrial Translocator Protein and Controls Steroidogenesis

Midzak

Akula

Lecanu

et al. 2011

Journal of Biological Chemistry

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“…The cells also expressed P450scc and mitochondrial benzodiazepine receptor (MBR, also called peripheral benzodiazepine receptor) mRNA and protein . Like the StAR protein, the MBR is involved in the transport of cholesterol into the mitochondria and agonists of this receptor have been shown to increase the synthesis of steroids (Culty et al, 1999;Stocco, 2001).…”

Section: Steroids In the Aging Nervous System: The Endocrine Glands Amentioning

confidence: 99%

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

Schumacher

Weill-Engerer

Lière

et al. 2003

Progress in Neurobiology

269

171

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Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the ␤-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to 5-androstene-3␤,17␤-diol and to 7␣-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of ␤-amyloid deposits.

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In vitro studies on the role of the peripheral-type benzodiazepine receptor in steroidogenesis

Cited by 108 publications

References 42 publications

A Farnesylated Coxiella burnetii Effector Forms a Multimeric Complex at the Mitochondrial Outer Membrane during Infection

A Farnesylated Coxiella burnetii Effector Forms a Multimeric Complex at the Mitochondrial Outer Membrane during Infection

Novel Androstenetriol Interacts with the Mitochondrial Translocator Protein and Controls Steroidogenesis

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

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