Osteopetrosis Mutation R444L Causes Endoplasmic Reticulum Retention and Misprocessing of Vacuolar H+-ATPase a3 Subunit

Bhargava, Ajay; Voronov, Irina; Wang, Yongqiang; Glogauer, Michael; Kartner, Norbert; Manolson, Morris F.

doi:10.1074/jbc.m112.345702

Cited by 33 publications

(28 citation statements)

References 53 publications

(30 reference statements)

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“…It was recently demonstrated that glycosylation of residue R444 in V0a3, an osteoclast specific V0a isoform, is required for its proper delivery to lysosomes (Bhargava et al, 2012). To investigate the role of glycosylation on the V0a1 subunit, we generated an R447L mutant analogous to the R444L mutation in V0a3, using a C-terminal flag tagged V0a1 (V0a1-flag) that enabled the mutant to be differentiated from endogenous V0a1 subunit in murine neuroblastoma (N2a) cells.…”

Section: Resultsmentioning

confidence: 99%

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

et al. 2015

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Summary Presenilin-1 (PS1) deletion or Alzheimer’s Disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in PS1KO cells induces abnormal Ca2+ efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca2+. In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca2+ homeostasis, but correcting lysosomal Ca2+ deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss of function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca2+ homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism.

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Section: Resultsmentioning

confidence: 99%

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

et al. 2015

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“…In less common cases, lysosomal dysfunction arises through mutations in genes encoding proteins that reside in another organelle but impact the function of a lysosomal constituent as their primary disease effect. Examples include osteopetrosis (Bhargava et al, 2012), Wolfram Syndrome (Gharanei et al, 2013), and PS1-FAD (Lee et al, 2010a; Lee et al, 2015), all of which are disorders where the mutated protein residing in the ER impairs the stability, delivery, or function of a lysosomal constituent. While most LSDs involve dysfunction of proteins that are ubiquitous in lysosomes throughout the body, it is remarkable that many LSDs have particularly devastating effects on the CNS.…”

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

“…One of these mutations was shown to impair maturation and processing of V0a3 in osteoclasts. The mutated V0a3 is retained in the ER instead of being localized to lysosomes where it would normally be integrated as part of the v-ATPase (Bhargava et al, 2012). In addition to V0a3 being a component of the lysosomal v-ATPase, osteoclasts express the V0a3 isoform of the V0a subunit and use the v-ATPase to acidify extracellular compartments for bone reabsorption (Toyomura et al, 2003).…”

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Colacurcio

Nixon

2016

Ageing Research Reviews

372

304

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Autophagy and endocytosis deliver unneeded cellular materials to lysosomes for degradation. Beyond processing cellular waste, lysosomes release metabolites and ions that serve signaling and nutrient sensing roles, linking the functions of the lysosome to various pathways for intracellular metabolism and nutrient homeostasis. Each of these lysosomal behaviors is influenced by the intraluminal pH of the lysosome, which is maintained in the low acidic range by a proton pump, the vacuolar ATPase (v-ATPase). New reports implicate altered v-ATPase activity and lysosomal pH dysregulation in cellular aging, longevity, and adult-onset neurodegenerative diseases, including forms of Parkinson Disease and Alzheimer Disease. Genetic defects of subunits composing the v-ATPase or v-ATPase-related proteins occur in an increasingly recognized group of familial neurodegenerative diseases. Here, we review the expanding roles of the v-ATPase complex as a platform regulating lysosomal proteolysis and cellular homeostasis. We discuss the unique vulnerability of neurons to persistent low level lysosomal dysfunction and review recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum.

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“…, the a subunit is misfolded, unglycosylated, retained in the ER, and ultimately subjected to proteolytic degradation (20). It was of interest, therefore, to determine whether the cutis laxa and dRTA mutations have similar impacts on a2 and a4 subunits, respectively, using methods for assessing N-glycosylation and stability that were previously described (25).…”

Section: R444lmentioning

confidence: 99%

“…For example, mutations affecting the function of a2 result in cutis laxa (wrinkled skin syndrome), where aberrant Golgi function results in glycosylation defects with consequent abnormal elastin processing that affects skin and internal organs (16)(17)(18). Mutations that affect a3 function result in inability of osteoclasts to resorb bone, causing autosomal malignant osteopetrosis that is characterized by dense, brittle bone (19,20). Loss of a4 function due to mutation results in distal renal tubular acidosis (dRTA) with occasional hearing loss (21,22) Here we focus on the effect of human mutations on a2 traffic to Golgi and a4 traffic to the plasma membrane based on their proposed in vivo locations and functions.…”

mentioning

confidence: 99%

Molecular mechanisms of cutis laxa– and distal renal tubular acidosis–causing mutations in V-ATPase a subunits, ATP6V0A2 and ATP6V0A4

Esmail

Kartner

Yao

et al. 2018

Journal of Biological Chemistry

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The a subunit is the largest of 15 different subunits that make up the vacuolar H + -ATPase (V-ATPase) complex, where it functions in proton translocation. In mammals, this subunit has four paralogous isoforms, a1-a4, which may encode signals for targeting assembled VATPases to specific intracellular locations. Despite the functional importance of the a subunit, its structure remains controversial. By studying molecular mechanisms of human disease-causing missense mutations within a subunit isoforms, we may identify domains critical for V-ATPase targeting, activity and/or regulation.cDNA . Coimmunoprecipitation studies revealed an increase in association of a4 R449H with the V0 assembly factor VMA21, and a reduced association with the V1 sector subunit, ATP6V1B1 (B1). For a4 G820R , where stability, degradation and trafficking were relatively unaffected, 3D molecular modeling suggested that the mutation causes dRTA by blocking the proton pathway. This study provides critical information that may assist rational drug design to manage dRTA and cutis laxa. Vacuolar H+ -ATPases (V-ATPases) are conserved, multisubunit rotary proton pumps that play crucial roles in regulating the pH of cells and their intracellular compartments (1-5). They can be categorized as endomembrane or plasma membrane V-ATPases, based on their subcellular localization (6,7). Endomembrane V-ATPases are expressed in all eukaryotic cells in the membranes of acidic organelles like lysosomes, endosomes and the Golgi apparatus, where they translocate protons to acidify the luminal compartments of the organelles (8). Plasma membrane V-ATPases traffic to the surfaces of some specialized cells, such as osteoclasts, kidney intercalated cells and metastatic cancer cells, where they secrete protons into the extracellular fluid (6,9-11).The V-ATPase complex consists of 15 different subunits arranged into two major sectors, the http://www.jbc.org/cgi

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Osteopetrosis Mutation R444L Causes Endoplasmic Reticulum Retention and Misprocessing of Vacuolar H+-ATPase a3 Subunit

Cited by 33 publications

References 53 publications

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Molecular mechanisms of cutis laxa– and distal renal tubular acidosis–causing mutations in V-ATPase a subunits, ATP6V0A2 and ATP6V0A4

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