Mesencephalic Astrocyte-derived Neurotrophic Factor Protects the Heart from Ischemic Damage and Is Selectively Secreted upon Sarco/endoplasmic Reticulum Calcium Depletion

Glembotski, Christopher C.; Thuerauf, Donna J.; Huang, Cai; Vekich, John A.; Gottlieb, Roberta A.; Doroudgar, Shirin

doi:10.1074/jbc.m112.356345

Cited by 181 publications

(241 citation statements)

References 73 publications

Supporting

Mentioning

225

Contrasting

Order By: Relevance

“…We also observed Tg-induced secretion of SP-GFP-RTDL, indicating a responsiveness of the C-terminal sequence to ER stress, independent of additional MANF sequences. This differs from the recently reported results from Glembotski et al, which found the RTDL sequence is not required for the secretory response of MANF to Tg-induced ER stress in HeLa and cardiomyocytes (11). In these cells, MANF secretion was shown to be regulated by a calcium-dependent interaction with GRP78 (BiP) in the ER.…”

Section: Discussioncontrasting

confidence: 99%

“…Removal of the C-terminal RTDL sequence increased secretion of the protein, consistent with the bulk flow of the MANF-⌬RTDL protein through the secretory pathway and a loss of retrograde trafficking from the Golgi to ER. These findings are consistent with recent reports, which show that removal of the RTDL sequence increases MANF secretion in non-neuronal cell types (11,14). We further examined the contribution of the RTDL sequence, independent of additional MANF sequences, using GFP constructs containing only the signal peptide and seven C-terminal amino acids, ASARTDL.…”

Section: Discussionsupporting

confidence: 90%

“…RTDL Sequence Mediates Secretory Responsiveness to Thapsigargin-induced ER Stress-MANF secretion is highly responsive to ER stress in HEK293, HeLa, and cardiomyocytes (8,9,11). These studies used Tg, a compound that causes ER stress by inhibiting the ER Ca 2ϩ -ATPase and depleting ER Ca 2ϩ levels (26).…”

Section: Gfp-tagged Manf Is Localized To the Er-mentioning

confidence: 99%

“…Additional clues to the function of MANF come from studies reporting the responsiveness of MANF expression and secretion to ER stress. Stress-induced transcriptional upregulation is driven by a type 2 ER stress-response element in the MANF promoter (10), and increased secretion was observed in HEK293, HeLa, and cardiomyocytes in response to ER stress-inducing molecules (8,9,11).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors

Henderson

Richie

Airavaara

et al. 2013

Journal of Biological Chemistry

133

177

View full text Add to dashboard Cite

Background: Mesencephalic astrocyte-derived neurotrophic factor is a secreted protein with an unknown mechanism of action. Results: KDEL-like sequence of MANF ("RTDL") is required for ER retention, secretory responsiveness to ER stress, and surface binding. Conclusion: KDEL receptors modulate secretion and surface binding of MANF. Significance: The plasma membrane localization of KDELRs has implications for MANF and other KDEL-containing proteins.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 90%

Section: Gfp-tagged Manf Is Localized To the Er-mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors

Henderson

Richie

Airavaara

et al. 2013

Journal of Biological Chemistry

133

177

View full text Add to dashboard Cite

show abstract

“…On the other hand, it is reported that the secretion of CRELD2 and MANF is not accompanied with the magnitude of ER stress. 12,13,25,28,29) It is therefore considered that there would be more complicated relationships between the CRELD2 and MANF proteins to regulate their secretion.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Role of MANF in Regulating the Secretion of CRELD2

Oh‐hashi

Norisada

Hirata

et al. 2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

We recently demonstrated that the secretion of two novel endoplasmic reticulum (ER) stress-inducible proteins, cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) and mesencephalic astrocyte-derived neurotrophic factor (MANF), are oppositely regulated by the overexpression of 78 kDa glucose-regulated protein (GRP78). In the present study, we found that the co-transfection of CRELD2 and MANF remarkably enhanced the secretion of CRELD2 without affecting the expression level of GRP78. To identify the structural features of CRELD2 and MANF involved in this process, we generated several CRELD2 and MANF expression constructs. The deletion of the four C-terminal amino acids, either REDL in CRELD2 or RTDL in MANF, abolished the increased secretion of CRELD2 induced by the co-expression of MANF. The deleted mutation of MANF partially abolished the increased secretion of wild type CRELD2 (wtCRELD2) as a positive action of wild type MANF (wtMANF), even when we added the amino acid sequence RTDL at the C-terminus of each mutated MANF construct. Enhanced green fluorescent protein (EGFP), which was tagged with the signal peptide sequence at the N-terminus and four C-terminal amino acids (KEDL, REDL or RTDL), were retained intracellularly, but they did not enhance the secretion of wtCRELD2. Taken together, our data demonstrate that MANF is a factor in regulating the secretion of CRELD2 through four C-terminal amino acids, RTDL and REDL, and the fluctuation of intracellular MANF seems to potentiate the secretion of CRELD2.Key words endoplasmic reticulum; chaperone; 78 kDa glucose-regulated protein (GRP78); cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2); mesencephalic astrocyte-derived neurotrophic factor (MANF)The folding and modification of newly synthesized transmembrane and secretory proteins in the endoplasmic reticulum (ER) is maintained by a variety of mechanisms.1,2) Under some pathophysiological conditions, certain ER functions become disordered and then unfolded and/or misfolded proteins are accumulated in the ER.3,4) Abnormal protein retention results in ER stress and activation of the three canonical ERresident stress sensors; protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), 5) inositol-requiring enzyme 1 (IRE1) 6) and activating transcription factor 6 (ATF6), 7) induces a variety of genes.8-12) Among them, growth arrest and DNA damage-inducible protein 153 (GADD153) is well-known to promote stress-induced cell death by activating caspases. 8,9) ER resident molecular chaperones such as 78 kDa glucoseregulated protein (GRP78) are reported to alleviate the stress by properly folding and degrading unfolded proteins and attenuating ER stress signals. 10,11) We previously identified the cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) gene as a novel ER stress-inducible gene and demonstrate that ATF6 positively regulates the transcription of the CRELD2 gene through a well-conserved ER stress response element (ERSE) in the proximal regio...

show abstract

Functional analysis of mesencephalic astrocyte‐derived neurotrophic factor in retinal ganglion cells under oxidative stress

Komatsu

Okumichi

et al. 2020

Cell Biochemistry & Function

View full text Add to dashboard Cite

Glaucoma is optic neuropathy that is characterized by progressive neurodegeneration of the retinal ganglion cells (RGCs) and axons. This condition will lead to visual impairment and bring glaucoma to become the second cause of blindness globally. Neuroprotection in glaucoma is needed to prevent the progression of optic neuropathy. In this study, we examined the effects of the superior colliculus (SC), and mesencephalic astrocyte‐derived neurotrophic factor (MANF) secreted from the SC, on RGC survival after oxidative stress. SC slices and RGCs from rats (3‐day old) were co‐cultured using a 3D‐transwell system. In addition, primary RGCs from 4 to 5‐day‐old rats were cultured and treated with 100 μM hydrogen peroxide (H2O2), together with stimulation by MANF. Immunoblot and immunofluorescence analyses indicated down‐regulated expression levels of several survival markers of RGCs. Extension of neurites was decreased in RGCs treated with 100 μM H2O2. Following co‐culture with SC slices, or the addition of MANF, we found that both the down‐regulated expression of neural markers and extension of neurites caused by oxidative stress in RGCs were blocked. Furthermore, we found a decrease in the expression of neural markers and extension of neurites after co‐culture with MANF siRNA‐treated SC slices compared with slices treated with mock siRNA, but, RGCs co‐cultured with SC slices treated with MANF siRNA displayed no‐changed about to apoptosis. These results suggest that MANF secreted from the SC may play an important role in maintenance of function and survival of RGCs. It is also possible that MANF is an important factor in neuroprotection of RGCs. Significance of the Study Glaucoma is a progressive neurodegenerative disease of the retinal ganglion cell (RGC) and their axons. Neuroprotection is aimed at protecting those neurons that are damaged glaucomatous optic neuropathy. We have now examined the effects of superior colliculus, or msencephalic astrocyte‐derived neutrophic factor (MANF), secreted from superior colliculus, on RGC survival using co‐culture system. Our results suggested that MANF may important key factor in neuroprotection of RGC.

show abstract

Mesencephalic Astrocyte-derived Neurotrophic Factor Protects the Heart from Ischemic Damage and Is Selectively Secreted upon Sarco/endoplasmic Reticulum Calcium Depletion

Cited by 181 publications

References 73 publications

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors

Characterization of the Role of MANF in Regulating the Secretion of CRELD2

Functional analysis of mesencephalic astrocyte‐derived neurotrophic factor in retinal ganglion cells under oxidative stress

Contact Info

Product

Resources

About