<scp>AMOT</scp>130 linking F‐actin to <scp>YAP</scp> is involved in intervertebral disc degeneration

Zhang, Cong; Wang, Feng; Xie, Zhi‐Yang; Chen, Lu; Sinkemani, Arjun; Yu, Hui

doi:10.1111/cpr.12492

Cited by 23 publications

(18 citation statements)

References 36 publications

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“…Since the cytoplasmic vacuoles take up a large percentage of cell volume and NNPC are morphologically different from nonvacuolated CNPC [Hunter et al, 2003b;Kim et al, 2009b], it is not unreasonable to presume that by altering the organization and components of cytoskeletal proteins, these vacuous inclusions might modulate the Hippo-Yap signals in a similar manner as the cell contact or the high density attenuates cell growth. In support of this notion, we have revealed that the nuclear localization of YAP requires the integrity of the F-actin cytoskeleton in rat CNPC; moreover, LATS (large tumor suppressor homologs)-mediated YAP regulation by Hippo signals is also dependent on the integrity of F-actin, indicating that large cytoplasmic vacuoles and the altered cytoskeleton are closely related to regulation of Hippo-YAP and control cell proliferation in NNPC [Zhang et al, 2018].…”

Section: Evaluation Of the Hypothesismentioning

confidence: 56%

“…In support of this notion, as rat IVD matures the cartilaginous matrix accumulates while the ratio of NNPC gradually decreases [Wang et al, , 2016Zhang et al, 2017Zhang et al, , 2018. Besides, compared to large and vacuolated NNPC, smaller nonvacuolated CNPC express higher levels of type I collagen, biglycan, and tissue inhibitor of metalloproteinases (MMP)-1 [Chen et al, 2006].…”

Section: Evaluation Of the Hypothesismentioning

confidence: 88%

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Large Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation

Hong

Zhang

Wang

et al. 2018

Cells Tissues Organs

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Degeneration of the intervertebral disc, which is closely associated with the loss of vacuolated notochordal nucleus pulposus cells (NNPC), remains a major cause of lower-back pain and motor deficiency. Being the most defining characteristic of NNPC, large cytoplasmic vacuoles not only modulate the cytoskeleton and shape cell morphology but they also respond to the disc microenvironment and regulate the biological behavior of vacuolated cells as a potent reporter of the histocytological changes that occur at the beginning of disc aging and degeneration. Here we hypothesize a model in which large cytoplasmic vacuoles primarily function to maintain a reasonable intracellular pressure (P_v) that facilitates NNPC in resisting the extracellular mechanical loading (P_e), part of which is absorbed by the extracellular matrix (P_m), forming the equation P_e = P_m + P_v. By mimicking a situation of contact-induced growth inhibition, the crowded cytoplasmic vacuoles slow down the proliferation of NNPC and restrain the generation of nonvacuolated chondrocytic nucleus pulposus cells (CNPC), whereas increased mechanical loading (↑P_e) alters cytoskeletons and breaches cytoplasmic vacuoles, which in turn weakens the vacuoles-mediated proliferation check, increases the generation of CNPC that accumulates fibrocartilaginous matrix, and rebalances the increased loading with elevated P_m (↑P_m) and lowered P_v (↓P_v), equating to ↑P_e = ↑P_m + ↓P_v. By depicting the biological function and the disappearance of the cytoplasmic vacuoles, our model highlights a mechanical exhaustion of the notochordal cell resources, which might help to elucidate the histocytological changes that initiate disc aging and degeneration.

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Section: Evaluation Of the Hypothesismentioning

confidence: 56%

Section: Evaluation Of the Hypothesismentioning

confidence: 88%

Large Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation

Hong

Zhang

Wang

et al. 2018

Cells Tissues Organs

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“…Thus, it is possible that modular competition between PPxY motifs of filoviral VP40 and Amot for binding to the WW domain of YAP1 could impact several processes in the host cell including: 1) actin dynamics and polymerization, 2) tight junction formation and integrity, and 3) upregulation of cell proliferation genes (Fig 12). Our data indicate that competition for binding among YAP1/Amot/mVP40 complexes, as well as Amot's role in regulating F-actin dynamics at the plasma membrane [62,90], may both play a mechanistic role in impacting VP40-mediated egress.…”

Section: Discussionmentioning

confidence: 82%

“…Amot binds and sequesters YAP1 on both actin filaments and at cellular tight junctions (Fig 12) [59,60,62,64,65,[89][90][91][92][93][94]. The Amot/YAP1 complex may also enter the nucleus leading to upregulation of a set of genes that may be distinct from those upregulated by YAP1 alone [61,64,66].…”

Section: Discussionmentioning

confidence: 99%

Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding

et al. 2020

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Ebola (EBOV) and Marburg (MARV) are members of the Filoviridae family, which continue to emerge and cause sporadic outbreaks of hemorrhagic fever with high mortality rates. Filoviruses utilize their VP40 matrix protein to drive virion assembly and budding, in part, by recruitment of specific WW-domain-bearing host proteins via its conserved PPxY Late (L) domain motif. Here, we screened an array of 115 mammalian, bacterially expressed and purified WW-domains using a PPxY-containing peptide from MARV VP40 (mVP40) to identify novel host interactors. Using this unbiased approach, we identified Yes Associated Protein (YAP) and Transcriptional co-Activator with PDZ-binding motif (TAZ) as novel mVP40 PPxY interactors. YAP and TAZ function as downstream transcriptional effectors of the Hippo signaling pathway that regulates cell proliferation, migration and apoptosis. We demonstrate that ectopic expression of YAP or TAZ along with mVP40 leads to significant inhibition of budding of mVP40 VLPs in a WW-domain/PPxY dependent manner. Moreover, YAP colocalized with mVP40 in the cytoplasm, and inhibition of mVP40 VLP budding was more pronounced when YAP was localized predominantly in the cytoplasm rather than in the nucleus. A key regulator of YAP nuclear/cytoplasmic localization and function is angiomotin (Amot); a multi-PPxY containing protein that strongly interacts with YAP WW-domains. Interestingly, we found that expression of PPxY-containing Amot rescued mVP40 VLP egress from either YAP-or TAZ-mediated inhibition in a PPxY-dependent manner. Importantly, using a stable Amot-knockdown cell line, we found that expression of Amot was critical for efficient egress of mVP40 VLPs as well as egress and spread of authentic MARV in infected cell cultures. In sum, we identified novel negative (YAP/TAZ) and positive (Amot) regulators of MARV VP40-mediated egress, that likely function in part, via competition between host and viral PPxY motifs binding to modular host WW-domains. These findings

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“…YAP inhibition seems to occur by cell-to-cell contact in IVD cells [ 145 ]. Remarkably, while the expression of YAP decreases with age [ 146 ], YAP silencing was shown to promote NP cell senescence [ 145 ], which adds to the difficulty to duly apprehend the variation of disc cell regulation, upon multifactorial simulation and aging.…”

Section: Ivd Cell Activity and Molecular Biology In Health And Dismentioning

confidence: 99%

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Baumgartner

Wuertz‐Kozak

Maitre

et al. 2021

IJMS

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Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations’ processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.

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AMOT130 linking F‐actin to YAP is involved in intervertebral disc degeneration

Abstract: This study showed that a mechanism by which Hippo pathway and F-actin synergize to modulate YAP activation and localization in the context of IDD and help to control NPCs proliferation.

Cited by 23 publications

References 36 publications

Large Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation

Large Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation

Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

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