MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP

Yan, Yahui; Rato, Cláudia; Rohland, Lukas; Preißler, Steffen; Ron, David

doi:10.1038/s41467-019-08450-4

Cited by 79 publications

(91 citation statements)

References 62 publications

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“…Consistent with our network, MANF has conserved, divergent genetic interactions with XBP1 and EIF2AK3, but not ATF6 (Lindstrom et al, 2016). Moreover, MANF was recently identified to stabilize a subset of HSPA5-client complexes in the ER lumen (Yan et al, 2019). Indeed, HSPA5 is highly coessential with MANF in addition to correlating with XBP1 and anticorrelating with EIF2AK3, supporting a model in which MANF is a point of regulation between the functionally differentiated branches of the UPR.…”

Section: Identifying Topology and Crosstalk Between Functional Modulesupporting

confidence: 86%

Coessential Genetic Networks Reveal the Organization and Constituents of a Dynamic Cellular Stress Response

Amici¹,

Jackson²,

Metz³

et al. 2019

Preprint

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The interrelated programs essential for cellular fitness in the face of stress are critical to understanding tumorigenesis, neurodegeneration, and aging. However, modelling the combinatorial landscape of stresses experienced by diseased cells is challenging, leaving functional relationships within the global stress response network incompletely understood. Here, we leverage genome-scale fitness screening data from 625 cancer cell lines, each representing a unique biological context, to build a network of "coessential" gene relationships centered around master regulators of the response to proteotoxic, oxidative, hypoxic, and genotoxic stress. This approach organizes the stress response into functional modules, identifies genes connecting distinct modules, and reveals mechanisms underlying cellular dependence on individual modules. As an example of the power of this approach, we discover that the previously unannotated HAPSTR (C16orf72) promotes resilience to diverse stressors as a stress-inducible regulator of the E3 ligase HUWE1. Altogether, we present a broadly applicable framework and interactive tool (http://fireworks.mendillolab.org/) to interrogate biological networks using unbiased genetic screens.

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Section: Identifying Topology and Crosstalk Between Functional Modulesupporting

confidence: 86%

Coessential Genetic Networks Reveal the Organization and Constituents of a Dynamic Cellular Stress Response

Amici¹,

Jackson²,

Metz³

et al. 2019

Preprint

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“…Manf inactivation causes upregulation of ER stress and UPR markers in the cochlear sensory cells MANF physically interacts with the ER chaperone GRP78 and this complex antagonizes ER stress caused by protein folding defects 7,8 . To find out if GRP78 is upregulated in Manf-inactivated cochleas, similar as shown in the pancreas 4 , we stained cochlear sections from 8-weekold mice with the GRP78 antibody.…”

Section: Conditional Inactivation Suggests a Local Function For Manf mentioning

confidence: 99%

“…MANF resides in the endoplasmic reticulum (ER) where it promotes protein-folding homeostasis 6 . MANF interacts physically with the major ER chaperone, the 78 kDa glucose-regulated protein (GRP78; also known as the binding immunoglobulin protein, BiP) 7,8 . Proteostasis defects trigger GRP78 and MANF upregulation, in conjunction with the activation of the unfolded protein response (UPR) and calcium release from the ER stores 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss

et al. 2020

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The non-conventional neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that promotes ER homeostasis. MANF has a cytoprotective function, shown in the central nervous system neurons and pancreatic beta cells. Here, we report that MANF is expressed in the hair cells and neurons and in selected non-sensory cells of the cochlea and that Manf inactivation triggers upregulation of the ER chaperones in these cells. However, Manf inactivation resulted in the death of only outer hair cells (OHCs), the cells responsible for sound amplification in the cochlea. All OHCs were formed in Manf-inactivated mice, but progressive OHC death started soon after the onset of hearing function. The robust OHC loss was accompanied by strongly elevated hearing thresholds. Conditional Manf inactivation demonstrated that MANF has a local function in the cochlea. Immunostainings revealed the upregulation of CHOP, the pro-apoptotic component of the unfolded protein response (UPR), in Manf-inactivated OHCs, linking the UPR to the loss of these cells. The phenotype of Manf-inactivated OHCs was distinctly dependent on the mouse strain, such that the strains characterized by early-onset age-related hearing loss (C57BL/6J and CD-1) were affected. These results suggest that Manf deficiency becomes detrimental when accompanied by gene mutations that predispose to hearing loss, by intensifying ER dyshomeostasis. Together, MANF is the first growth factor shown to antagonize ER stress-mediated OHC death. MANF might serve as a therapeutic candidate for protection against hearing loss induced by the ER-machinery-targeting stressors.

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“…We previously showed that Grp78 and MANF interact directly with each other in cardiac myocytes 14,15 . Moreover, another study has shown that MANF interacts with Grp78 in vitro in a way that affects the chaperone activity of Grp78 in a manner predicted to improve ER proteostasis, in vivo 63 . In combination with that study, our results here demonstrate that MANF can improve ER protein-folding by interacting with Grp78, and MANF can act as a chaperone itself, suggesting that there may be multiple ways that MANF improves ER protein-folding and cardiac myocyte viability during reductive stresses, such as I/R and DTT.…”

Section: Manf Represents a Novel Class Of Chaperonesmentioning

confidence: 99%

Mesencephalic astrocyte–derived neurotrophic factor is an ER-resident chaperone that protects against reductive stress in the heart

Arrieta

Blackwood

Stauffer

et al. 2020

Journal of Biological Chemistry

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We have previously demonstrated that ischemia/reperfusion (I/R) impairs endoplasmic reticulum (ER)-based protein folding in the heart and thereby activates an unfolded protein response sensor and effector, activated transcription factor 6α (ATF6). ATF6 then induces mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER-resident protein with no known structural homologs and unclear ER function. To determine MANF's function in the heart in vivo, here we developed a cardiomyocyte-specific MANF-knockdown mouse model. MANF knockdown increased cardiac damage after I/R, which was reversed by AAV9-mediated ectopic MANF expression. Mechanistically, MANF knockdown in cultured neonatal rat ventricular myocytes (NRVMs) impaired protein folding in the ER and cardiomyocyte viability during simulated I/R. However, this was not due to MANF-mediated protection from reactive oxygen species generated during reperfusion. Because I/R impairs oxygen-dependent ER protein disulfide formation and such impairment can be caused by reductive stress in the ER, we examined the effects of the reductive ER stressor DTT. MANF knockdown in NRVMs increased cell death from DTT-mediated reductive ER stress, but not from nonreductive ER stresses caused by thapsigargin-mediated ER Ca2+ depletion or tunicamycin-mediated inhibition of ER protein glycosylation. In vitro, recombinant MANF exhibited chaperone activity that depended on its conserved cysteine residues. Moreover, in cells, MANF bound to a model ER protein exhibiting improper disulfide bond formation during reductive ER stress but did not bind to this protein during nonreductive ER stress. We conclude that MANF is an ER chaperone that enhances protein folding and myocyte viability during reductive ER stress.

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MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP

Cited by 79 publications

References 62 publications

Coessential Genetic Networks Reveal the Organization and Constituents of a Dynamic Cellular Stress Response

Coessential Genetic Networks Reveal the Organization and Constituents of a Dynamic Cellular Stress Response

Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss

Mesencephalic astrocyte–derived neurotrophic factor is an ER-resident chaperone that protects against reductive stress in the heart

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