Induction Profile of MANF/ARMET by Cerebral Ischemia and its Implication for Neuron Protection

Yan, Yu; Liu, Lian-Cheng; Fa-cai, Wang; Liang, Yan; Cha, Daqin; Zhang, Jingjing; Shen, Yujun; Wang, Haiping; Fang, Shengyun

doi:10.1038/jcbfm.2009.181

Cited by 98 publications

(100 citation statements)

References 36 publications

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“…MANF was identified as a secreted protein from a cell line of astrocyte origin (1); however, subsequent studies found that neurons express the highest levels of MANF in the brain (12,39). MANF is also expressed in non-neuronal tissue, with widespread distribution and the highest expression generally found in tissues with a large secretory function, e.g.…”

Section: Discussionmentioning

confidence: 99%

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

131

177

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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.

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Section: Discussionmentioning

confidence: 99%

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

131

177

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“…It is suspected that the different localization of CHOP depends on the state of the cells and the intensity of the stress effect (56). In wt virus-infected cells, CHOP was detected in the nuclei of the majority of the cells, indicating severe ER stress, while in SAT Ϫ virus-infected cells, CHOP was also expressed, but to a lesser extent (41% of SAT Ϫ virus-infected cells versus 76% of wt-infected cells), and its localization remained perinuclear (Fig.…”

Section: Discussionmentioning

confidence: 99%

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Mészáros

Tóth

Olasz

et al. 2017

J Virol

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The SAT protein (SATp) of porcine parvovirus (PPV) accumulates in the endoplasmic reticulum (ER), and SAT deletion induces the slow-spreading phenotype. The in vitro comparison of the wild-type Kresse strain and its SAT knockout (SAT Ϫ ) mutant revealed that prolonged cell integrity and late viral release are responsible for the slower spreading of the SAT Ϫ virus. During PPV infection, regardless of the presence or absence of SATp, the expression of downstream ER stress response proteins (Xbp1 and CHOP) was induced. However, in the absence of SATp, significant differences in the quantity and the localization of CHOP were detected, suggesting a role of SATp in the induction of irreversible ER stress in infected cells. The involvement of the induction of irreversible ER stress in porcine testis (PT) cell necrosis and viral egress was confirmed by treatment of infected cells by ER stressinducing chemicals (MG132, dithiothreitol, and thapsigargin), which accelerated the egress and spreading of both the wild-type and the SAT Ϫ viruses. UV stress induction had no beneficial effect on PPV infection, underscoring the specificity of ER stress pathways in the process. However, induction of CHOP and its nuclear translocation cannot alone be responsible for the biological effect of SAT, since nuclear CHOP could not complement the lack of SAT in a coexpression experiment. IMPORTANCE SATp is encoded by an alternative open reading frame of the PPV genome. Earlier we showed that SATp of the attenuated PPV NADL-2 strain accumulates in the ER and accelerates virus release and spreading. Our present work revealed that slow spreading is a general feature of SAT Ϫ PPVs and is the consequence of prolonged cell integrity. PPV infection induced ER stress in infected cells regardless of the presence of SATp, as demonstrated by the morphological changes of the ER and expression of the stress response proteins Xbp1 and CHOP. However, the presence of SATp made the ER stress more severe and accelerated cell death during infection, as shown by the higher rate of expression of CHOP and alteration of the localization of CHOP. The beneficial effect of irreversible ER stress on PPV spread was confirmed by treatment of infected cells with ER stress-inducing chemicals.KEYWORDS CHOP, ER stress, SAT, Xbp1, alternative ORF, parvovirus, protoparvovirus, viral egress P orcine parvovirus (PPV) belongs to the species Ungulate protoparvovirus 1 in the genus Protoparvovirus. It is the causative agent of the stillbirth, mummification, embryonic death, infertility (SMEDI) syndrome in swine (1).A highly pathogenic strain with broad tissue tropism, strain Kresse, was isolated in the 1980s (2, 3). Kresse strain-infected piglets showed atypical signs of PPV infection, including necrotic lesions (4) on the lips, snout, tongue, and foot.The PPV single-stranded genome contains two major open reading frames (ORFs)

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“…In the last few years, it has been reported that the expression of CRELD2 and MANF are elevated in several physiological conditions, which are not restricted to the central nervous system. 23,[37][38][39] Therefore, further characterization of MANF and CRELD2 inside and outside cells under pathophysiological conditions may give new insights into the onset and progression of ER stress-related diseases. Fig.…”

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

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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...

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Induction Profile of MANF/ARMET by Cerebral Ischemia and its Implication for Neuron Protection

Cited by 98 publications

References 36 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

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

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

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