Soluble adenylyl cyclase is essential for proper lysosomal acidification

Rahman, Nawreen; Ramos‐Espiritu, Lavoisier; Milner, Teresa A.; Buck, Jochen; Levin, Lonny R.

doi:10.1085/jgp.201611606

Cited by 36 publications

(35 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that gp120 and TNFα have both been shown to neutralize endolysosome pH [ 34 – 36 ], we determined the extent to which gp120 and TNFα affected Tat-mediated LTR transactivation in the absence of chloroquine, and neither affected Tat-mediated LTR transactivation (Additional file 1 : Figure S2). However, we demonstrated that other endolysosome de-acidifying reagents acted in a similar way as chloroquine to enhance Tat-mediated LTR transactivation (Additional file 1 : Figure S2), and these reagents include LYS01 (a free base) [ 37 ], bafilomycin (a specific vacuolar ATPase inhibitor), and KH7 (a selective soluble adenylyl cyclase inhibitor) [ 38 ]. We showed that 100 μM of chloroquine enhanced Tat-mediated LTR transactivation at Tat concentration as low as 0.5 μg/ml (35 nM) (Additional file 1 : Figure S1).…”

Section: Resultsmentioning

confidence: 99%

Apolipoprotein E isoform dependently affects Tat-mediated HIV-1 LTR transactivation

Khan

Datta

Chen

2018

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundApolipoprotein E (ApoE) is the major carrier protein that mediates the transport and delivery of cholesterol and other lipids in the brain. Three isoforms of ApoE (ApoE2, ApoE3, ApoE4) exist in humans, and their relative expression levels impact HIV-1 infection, HIV-1/AIDS disease progression, and cognitive decline associated with HIV-1-associated neurocognitive disorder. Because HIV-1 Tat, a viral protein essential for HIV-1 replication, can bind to low-density lipoprotein receptor-related protein 1 (LRP1) that controls ApoE uptake in the brain, we determined the extent to which different isoforms of ApoE affected Tat-mediated HIV-1 LTR transactivation.MethodsUsing U87MG glioblastoma cells expressing LTR-driven luciferase, we determined the extent to which LRP1 as well as ApoE2, ApoE3, and ApoE4 affected Tat-mediated HIV-1 LTR transactivation.ResultsA specific LRP1 antagonist and siRNA knockdown of LRP1 both restricted significantly Tat-mediated LTR transactivation. Of the three ApoEs, ApoE4 was the least potent and effective at preventing HIV-1 Tat internalization and at decreasing Tat-mediated HIV-1 LTR transactivation. Further, Tat-mediated LTR transactivation was attenuated by an ApoE mimetic peptide, and ApoE4-induced restriction of Tat-mediated LTR transactivation was potentiated by an ApoE4 structure modulator that changes ApoE4 into an ApoE3-like phenotype.ConclusionsThese findings help explain observed differential effects of ApoEs on HIV-1 infectivity and the prevalence of HAND in people living with HIV-1 infection and suggest that ApoE mimetic peptides and ApoE4 structure modulator might be used as a therapeutic strategy against HIV-1 infection and associated neurocognitive disorders.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1129-1) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Apolipoprotein E isoform dependently affects Tat-mediated HIV-1 LTR transactivation

Khan

Datta

Chen

2018

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…There may be other sAC-defined cAMP compartments revealed by additional phenotypes in sAC KO MEFs. We have previously shown that sAC KO MEFs display a lysosomal acidification defect (Rahman et al, 2016) and are more susceptible to oncogenic transformation than wt cells (Ramos-Espiritu et al, 2016a). However, neither of these phenotypes has been ascribed to a specifically localized isoform of sAC, so it is unclear whether they define unique cAMP functional compartments.…”

Section: Discussionmentioning

confidence: 99%

“…We investigated mitochondrial bioenergetic properties in mitochondria isolated from sAC knockout (KO) mouse embryonic fibroblast (MEF) cell lines in which the enzyme had been genetically ablated, and mitochondria isolated from isogenic wild type (wt) control MEFs (Bitterman et al, 2013;Rahman et al, 2016;Ramos-Espiritu et al, 2016a,b). Complex I (CI) physiological activity [NADH:decylubiquinone (DBQ) oxidoreductase activity], was significantly decreased in sAC KO cells.…”

Section: Oxphos Is Impaired In Sac Knockout Mefsmentioning

confidence: 99%

Distinct intracellular sAC-cAMP domains regulate ER Ca2+ signaling and OXPHOS function

Valsecchi

Konràd

D'Aurelio

et al. 2017

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

cAMP regulates a wide variety of physiological functions in mammals. This single second messenger can regulate multiple, seemingly disparate functions within independently regulated cell compartments. We have previously identified one such compartment inside the matrix of the mitochondria, where soluble adenylyl cyclase (sAC) regulates oxidative phosphorylation (OXPHOS). We now show that sAC knockout fibroblasts have a defect in OXPHOS activity and attempt to compensate for this defect by increasing OXPHOS proteins. Importantly, sAC knockout cells also exhibit decreased probability of endoplasmic reticulum (ER) Ca release associated with diminished phosphorylation of the inositol 3-phosphate receptor. Restoring sAC expression exclusively in the mitochondrial matrix rescues OXPHOS activity and reduces mitochondrial biogenesis, indicating that these phenotypes are regulated by intramitochondrial sAC. In contrast, Ca release from the ER is only rescued when sAC expression is restored throughout the cell. Thus, we show that functionally distinct, sAC-defined, intracellular cAMP signaling domains regulate metabolism and Ca signaling.

show abstract

“…Recently, sAC’s control of the endosomal-lysosomal acidification has been shown to function in a PKA-dependent manner. The absence of sAC disrupts V-ATPase localization at the lysosomal membrane which is rescued by treatment with membrane-permeable cAMP [ 81 ]. It is interesting to note that a disturbance in lysosomal acidification through sAC knockout leads to an impaired autophagic degradative system.…”

Section: Functional Role Of Sac In Different Cellular Compartmentsmentioning

confidence: 99%

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

Pozdniakova

Ladilov

2018

JCDD

View full text Add to dashboard Cite

Mounting evidence confirms the compartmentalized structure of evolutionarily conserved 3′–5′-cyclic adenosine monophosphate (cAMP) signaling, which allows for simultaneous participation in a wide variety of physiological functions and ensures specificity, selectivity and signal strength. One important player in cAMP signaling is soluble adenylyl cyclase (sAC). The intracellular localization of sAC allows for the formation of unique intracellular cAMP microdomains that control various physiological and pathological processes. This review is focused on the functional role of sAC-produced cAMP. In particular, we examine the role of sAC-cAMP in different cellular compartments, such as cytosol, nucleus and mitochondria.

show abstract

Soluble adenylyl cyclase is essential for proper lysosomal acidification

Abstract: Lysosomes are the main degradative compartment in cells and require an acidic luminal environment for correct function. Rahman et al. show that soluble adenylyl cyclase is required for localization of the V-ATPase proton pump to lysosomes and therefore lysosomal acidification and function.

Cited by 36 publications

References 52 publications

Apolipoprotein E isoform dependently affects Tat-mediated HIV-1 LTR transactivation

Apolipoprotein E isoform dependently affects Tat-mediated HIV-1 LTR transactivation

Distinct intracellular sAC-cAMP domains regulate ER Ca2+ signaling and OXPHOS function

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

Contact Info

Product

Resources

About