Thioredoxin (Trx1) regulates CD4 membrane domain localization and is required for efficient CD4-dependent HIV-1 entry

Moolla, Naazneen; Killick, Mark; Papathanasopoulos, Maria A.; Capovilla, Alexio

doi:10.1016/j.bbagen.2016.05.030

Cited by 14 publications

(14 citation statements)

References 69 publications

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“…4C ), along with a variety of other A. baumannii - Acinetobacter calcoaceticus complex isolates ( Fig. S2 ), in M9 minimal medium (M9MM) supplemented with 1 mM membrane-impermeant dithionitrobenzoic acid (DTNB) to detect secreted reductase activity ( 8 , 37 ). DTNB was reduced to 2-nitro-5-thiobenzoic acid (TNB; yellow color) in the presence of the bacteria in a fashion similar to the positive reduction control β-mercaptoethanol (βME; a strong thiol-reducing agent).…”

Section: Resultsmentioning

confidence: 99%

Acinetobacter baumannii Gastrointestinal Colonization Is Facilitated by Secretory IgA Which Is Reductively Dissociated by Bacterial Thioredoxin A

Ketter

Guentzel

et al. 2018

mBio

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Multidrug-resistant Acinetobacter baumannii is among the most common causes of infectious complications associated with combat-related trauma in military personnel serving overseas. However, little is currently known about its pathogenesis. While the gastrointestinal (GI) tract has been found to be a major reservoir for A. baumannii, as well as to potentially contribute to development of multidrug resistance, no studies have addressed the mechanisms involved in gut colonization. In this study, we address this critical gap in knowledge by first assessing the interaction between secretory IgA (SIgA), the principal humoral immune defense on mucosal surfaces, and the A. baumannii clinical isolate Ci79. Surprisingly, SIgA appeared to enhance A. baumannii GI tract colonization, in a process mediated by bacterial thioredoxin A (TrxA), as evidenced by reduction of bacterial attachment in the presence of TrxA inhibitors. Additionally, a trxA targeted deletion mutant (ΔtrxA) showed reduced bacterial burdens within the GI tract 24 h after oral challenge by in vivo live imaging, along with loss of thiol-reductase activity. Surprisingly, not only was GI tract colonization greatly reduced but the associated 50% lethal dose (LD50) of the ΔtrxA mutant was increased nearly 100-fold in an intraperitoneal sepsis model. These data suggest that TrxA not only mediates A. baumannii GI tract colonization but also may contribute to pathogenesis in A. baumannii sepsis following escape from the GI tract under conditions when the intestinal barrier is compromised, as occurs with cases of severe shock and trauma.

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Section: Resultsmentioning

confidence: 99%

Acinetobacter baumannii Gastrointestinal Colonization Is Facilitated by Secretory IgA Which Is Reductively Dissociated by Bacterial Thioredoxin A

Ketter

Guentzel

et al. 2018

mBio

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“…In addition to inducing structural changes, changes to the redox state of CD4 also regulates CD4 membrane localization . Lateral movement of CD4 results in partitioning into different membrane microdomains, including detergent‐resistant membranes (DRMs)/“lipid rafts” and detergent‐soluble membranes (DSMs)/“non‐rafts” .…”

Section: Redox‐active Disulfidesmentioning

confidence: 99%

“…Lateral movement of CD4 results in partitioning into different membrane microdomains, including detergent‐resistant membranes (DRMs)/“lipid rafts” and detergent‐soluble membranes (DSMs)/“non‐rafts” . Importantly, the lateral movement of CD4 appears to be redox regulated, whereby inhibition of Trx‐1 induces translocation of CD4 into DRMs . CD4 localization in DRMs has been shown to be necessary for HIV infection .…”

Section: Redox‐active Disulfidesmentioning

confidence: 99%

From structure to redox: The diverse functional roles of disulfides and implications in disease

2017

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This review provides a comprehensive overview of the functional roles of disulfide bonds and their relevance to human disease. The critical roles of disulfide bonds in protein structure stabilization and redox regulation of protein activity are addressed. Disulfide bonds are essential to the structural stability of many proteins within the secretory pathway and can exist as intramolecular or inter-domain disulfides. The proper formation of these bonds often relies on folding chaperones and oxidases such as members of the protein disulfide isomerase (PDI) family. Many of the PDI family members catalyze disulfide-bond formation, reduction and isomerization through redox-active disulfides and perturbed PDI activity is characteristic of carcinomas and neurodegenerative diseases. In addition to catalytic function in oxidoreductases, redox-active disulfides are also found on a diverse array of cellular proteins and act to regulate protein activity and localization in response to oxidative changes in the local environment. These redox-active disulfides are either dynamic intramolecular protein disulfides or mixed disulfides with small-molecule thiols generating glutathionylation and cysteinylation adducts. The oxidation and reduction of redox-active disulfides are mediated by cellular reactive oxygen species and activity of reductases, such as glutaredoxin and thioredoxin. Dysregulation of cellular redox conditions and resulting changes in mixed disulfide formation are directly linked to diseases such as cardiovascular disease and Parkinson’s disease.

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“…Moreover, studies have indicated that the redox status of the structural disulfides of CD4 (i.e. in dithiol or disulfide form) have an essential role for the binding activity of CD4 to gp120 10–13 . Agents that inhibit thiol/disulfide exchange reactions have been shown to suppress HIV-1 viral entry suggesting that redox may be a rational target for HIV-1 treatment 8,9,12–16 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the thioredoxin system by PX-12 (1-methylpropyl 2-imidazolyl disulfide) impedes HIV-1 infection in TZM-bl cells

Lundberg

Mattsson

Reiser

et al. 2019

Sci Rep

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Human immunodeficiency virus (HIV-1) entry is initiated by the binding between the viral envelope glycoprotein gp120 and the host receptor CD4, and followed by reduction of structural disulfides of gp120 and CD4. The host thioredoxin-1 (Trx1) efficiently reduces disulfides of gp120 and CD4 in vitro , and recently CD4-dependent HIV-1 entry was shown to be inhibited by anti-Trx1-antibodies, indicating a central role for Trx1. 1-methylpropyl-2-imidazolyl disulfide (PX-12) is a reversible inhibitor of the Trx1 system that may also cause a slow irreversible thioalkylation of Trx1. It was developed as an antitumor agent, however, the current study aimed to determine if it also has an anti-HIV-1 effect. We show that PX-12 has anti-HIV-1(III B ) activity in TZM-bl cells, in fact, no virus was detected inside the cells in the presence of 10 µM PX-12. Moreover, PX-12 inhibited the enzymatic activity of Trx1 and the Trx1-dependent disulfide reduction of gp120. Microtubule polymerization and formation of acetylated microtubules were also inhibited, activities shown to be required for HIV-1 life cycle propagation. In conclusion, our data strengthens the notion that the early steps of the HIV-1 life cycle depends on the Trx1 system and indicate that the Trx1 system may be a rational drug target for HIV-1 treatment.

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Thioredoxin (Trx1) regulates CD4 membrane domain localization and is required for efficient CD4-dependent HIV-1 entry

Cited by 14 publications

References 69 publications

Acinetobacter baumannii Gastrointestinal Colonization Is Facilitated by Secretory IgA Which Is Reductively Dissociated by Bacterial Thioredoxin A

Acinetobacter baumannii Gastrointestinal Colonization Is Facilitated by Secretory IgA Which Is Reductively Dissociated by Bacterial Thioredoxin A

From structure to redox: The diverse functional roles of disulfides and implications in disease

Inhibition of the thioredoxin system by PX-12 (1-methylpropyl 2-imidazolyl disulfide) impedes HIV-1 infection in TZM-bl cells

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