V-ATPase a3 Subunit in Secretory Lysosome Trafficking in Osteoclasts

Nakanishi‐Matsui, Mayumi; Matsumoto, Naomi

doi:10.1248/bpb.b22-00371

Cited by 11 publications

(7 citation statements)

References 55 publications

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“…It specifically focuses on the bone-related gene ATP6V1H , previously identified by our research group, and its interaction with microgravity environments. ATP6V1H , known to be highly expressed in lysosomes, influences bone integrity by affecting osteoclast production and function [ 25 , 26 ]. Our prior research, including immunohistochemical staining and TRAP staining, revealed that ATP6V1H localizes in osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway

Zhao,

Wang,

et al. 2024

IJMS

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The microgravity conditions in outer space are widely acknowledged to induce significant bone loss. Recent studies have implicated the close relationship between Atp6v1h gene and bone loss. Despite this, the role of Atp6v1h in bone remodeling and its molecular mechanisms in microgravity have not been fully elucidated. To address this, we used a mouse tail suspension model to simulate microgravity. We categorized both wild-type and Atp6v1h knockout (Atp6v1h+/-) mice into two groups: regular feeding and tail-suspension feeding, ensuring uniform feeding conditions across all cohorts. Analysis via micro-CT scanning, hematoxylin-eosin staining, and tartrate-resistant acid phosphatase assays indicated that wild-type mice underwent bone loss under simulated microgravity. Atp6v1h+/- mice exhibited bone loss due to Atp6v1h deficiency but did not present aggravated bone loss under the same simulated microgravity. Transcriptomic sequencing revealed the upregulation of genes, such as Fos, Src, Jun, and various integrin subunits in the context of simulated microgravity and Atp6v1h knockout. Real-time quantitative polymerase chain reaction (RT-qPCR) further validated the modulation of downstream osteoclast-related genes in response to interactions with ATP6V1H overexpression cell lines. Co-immunoprecipitation indicated potential interactions between ATP6V1H and integrin beta 1, beta 3, beta 5, alpha 2b, and alpha 5. Our results indicate that Atp6v1h level influences bone loss in simulated microgravity by modulating the Fos-Jun-Src-Integrin pathway, which, in turn, affects osteoclast activity and bone resorption, with implications for osteoporosis. Therefore, modulating Atp6v1h expression could mitigate bone loss in microgravity conditions. This study elucidates the molecular mechanism of Atp6v1h’s role in osteoporosis and positions it as a potential therapeutic target against environmental bone loss. These findings open new possibilities for the treatment of multifactorial osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway

Zhao,

Wang,

et al. 2024

IJMS

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“…During this process of lysosomal exocytosis, lysosomes can migrate to the cell surface proximity and fuse with the plasma membrane, releasing their contents extracellularly. It has been reported that V-ATPase subunit ATP6AP1 regulates lysosomal trafficking and protease exocytosis in osteoclast-mediated bone resorption, and V-ATPase subunit V0a3 not only plays a critical role in V-ATPase activity but also is essential for anterograde trafficking of secretory lysosomes ( 37 , 38 ). These findings indicate that V-ATPase subunit expression and distribution are involved lysosomal exocytosis.…”

Section: Discussionmentioning

confidence: 99%

The role of lysosomes as intermediates in betacoronavirus PHEV egress from nerve cells

Wang,

He,

et al. 2023

J Virol

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The traditional view that betacoronaviruses exit occurs via the constitutive secretory route has recently been questioned by studies suggesting that this process involves lysosomal exocytosis. Here, we demonstrated that porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus, traffics to lysosomes prior to engaging in Arl8b-dependent lysosomal exocytosis. Notably, PHEV induces active or passive lysosomal acidification and activates lysosomal degradative enzymes. PHEV release depends on vacuolar H + -ATPase-mediated lysosomal acidification. In addition, PHEV transmission and PHEV-induced brain damage in the central nervous system can be blocked by the Rab7 GTPase competitive inhibitor CID1067700. Taken together, lysosome plays a critical role in PHEV egress in vitro and in vivo . IMPORTANCE Betacoronaviruses, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and mouse hepatitis virus (MHV), exploit the lysosomal exocytosis pathway for egress. However, whether all betacoronaviruses members use the same pathway to exit cells remains unknown. Here, we demonstrated that porcine hemagglutinating encephalomyelitis virus (PHEV) egress occurs by Arl8b-dependent lysosomal exocytosis, a cellular egress mechanism shared by SARS-CoV-2 and MHV. Notably, PHEV acidifies lysosomes and activates lysosomal degradative enzymes, while SARS-CoV-2 and MHV deacidify lysosomes and limit the activation of lysosomal degradative enzymes. In addition, PHEV release depends on V-ATPase-mediated lysosomal pH. Furthermore, this is the first study to evaluate βCoV using lysosome for spreading through the body, and we have found that lysosome played a critical role in PHEV neural transmission and brain damage caused by virus infection in the central nervous system. Taken together, different betacoronaviruses could disrupt lysosomal function differently to exit cells.

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“…Correct endosomal/lysosomal pH is critical for functions, such as cargo degradation and ligand receptor dissociation [ 94 , 95 ]. Rab7 has been implicated in V-ATPase function and endosomal acidification through direct interaction with the V 0 a 3 subunit in secretory lysosome trafficking [ 96 ] and by forming a ternary complex with RILP and the cytosolic V 1 G 1 subunit of the V 1 complex to regulate V 1 G 1 availability [ 97 ]. The data from the latter study suggest that RILP is responsible for the correct endosomal–lysosomal localization of V 1 G 1 and, thus, involved in regulating acidification [ 97 ].…”

Section: Rab7 Effectors and Physiologic Trka Trafficking And Degradationmentioning

confidence: 99%

Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot–Marie–Tooth 2B Disease

Mulligan,

Winckler

2023

Biomolecules

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Intracellular endosomal trafficking controls the balance between protein degradation and synthesis, i.e., proteostasis, but also many of the cellular signaling pathways that emanate from activated growth factor receptors after endocytosis. Endosomal trafficking, sorting, and motility are coordinated by the activity of small GTPases, including Rab proteins, whose function as molecular switches direct activity at endosomal membranes through effector proteins. Rab7 is particularly important in the coordination of the degradative functions of the pathway. Rab7 effectors control endosomal maturation and the properties of late endosomal and lysosomal compartments, such as coordination of recycling, motility, and fusion with downstream compartments. The spatiotemporal regulation of endosomal receptor trafficking is particularly challenging in neurons because of their enormous size, their distinct intracellular domains with unique requirements (dendrites vs. axons), and their long lifespans as postmitotic, differentiated cells. In Charcot–Marie–Tooth 2B disease (CMT2B), familial missense mutations in Rab7 cause alterations in GTPase cycling and trafficking, leading to an ulcero-mutilating peripheral neuropathy. The prevailing hypothesis to account for CMT2B pathologies is that CMT2B-associated Rab7 alleles alter endocytic trafficking of the neurotrophin NGF and its receptor TrkA and, thereby, disrupt normal trophic signaling in the peripheral nervous system, but other Rab7-dependent pathways are also impacted. Here, using TrkA as a prototypical endocytic cargo, we review physiologic Rab7 effector interactions and control in neurons. Since neurons are among the largest cells in the body, we place particular emphasis on the temporal and spatial regulation of endosomal sorting and trafficking in neuronal processes. We further discuss the current findings in CMT2B mutant Rab7 models, the impact of mutations on effector interactions or balance, and how this dysregulation may confer disease.

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V-ATPase a3 Subunit in Secretory Lysosome Trafficking in Osteoclasts

Cited by 11 publications

References 55 publications

Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway

Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway

The role of lysosomes as intermediates in betacoronavirus PHEV egress from nerve cells

Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot–Marie–Tooth 2B Disease

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