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

Henderson, Mark J.; Richie, Christopher T.; Airavaara, Mikko; Wang, Yun; Harvey, Brandon K.

doi:10.1074/jbc.m112.400648

Cited by 129 publications

(185 citation statements)

References 41 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…However, our study clearly demonstrate that the effect of MANF on CRELD2 secretion might not be simply due to competition between each C-terminal motif for binding to KDEL receptors. Henderson et al have reported KDEL receptors regulate the transport and secretion of MANF, 35) but the factors regulating the relationship between CRELD2 and MANF secretion remain to be determined. Therefore, further characterization of their relationship including KDEL receptors is required to reveal the novel mechanisms underlying the regulation of protein transport and secretion within the ER and Golgi apparatus.…”

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

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

show abstract

“…MANF also possesses an active endoplasmic reticulum retention signal at its C terminus, corroborating its anti-apoptotic activity (19).…”

Section: Discussionmentioning

confidence: 74%

“…Indeed, exogenously applied CDNF is able to prevent apoptosis in PC12 cells by modulating Bcl-2/Bax and caspase-3 activation (18). MANF also contains a functional KDEL endoplasmic reticulum retention signal at its C terminus, which binds to KDEL receptors both intracellularly and on the cell membrane (19). The removal of this C-terminal tetrapeptide motif can increase the secretion of MANF, which contributes to the hypothesis that MANF has at least two distinct targets: an intracellular target that is associated with the endoplasmic reticulum and an extracellular target.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

“…Henderson et al (19) showed that the C terminus of MANF (-RTDL) is essential for its retention in the endoplasmic reticulum and for its ability to bind plasma membranes, which depends on KDEL receptors. CDNF has a highly homologous sequence (-KTEL), which is exposed to solvent and has high conformational flexibility (Fig.…”

Section: Terminus Of Cdnf Possesses Active Sites That Are Conservedmentioning

confidence: 99%

See 1 more Smart Citation

The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers

Latge

Cabral

Oliveira

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic agent for treating Parkinson disease. Results: We determined the solution structure of CDNF and demonstrated its neuroprotective effects against insults caused by ␣-synuclein oligomers. Conclusion:We identified structural features of CDNF that might correspond with its physiological activity. Significance: This work strengthens the therapeutic relevance of using CDNF to treat neurodegenerative diseases.

show abstract

“…It protects neurons and controls the Parkinson's disease-like symptoms in rat 6-hydroxydopamine model. MANF was also identified as ER stress responsive protein and shown to suppress ER stress-induced cell death [37][38][39]. The interaction between MANF and RTN1-C was confirmed not only by retesting in yeast using both β-galactosidase assay and growth studies on selective media, but also by the immunoprecipitation assay and a subcellular co-localization assay in nerve cells.…”

Section: Discussionmentioning

confidence: 85%

Identification of MANF as a protein interacting with RTN1-C

Chen¹,

Wan²,

Du³

et al. 2015

ABBS

View full text Add to dashboard Cite

Reticulons (RTNs) constitute a family of endoplasmic reticulum (ER)-associated proteins with a reticular distribution. Recently, evidence has shown that they exert a cancer-specific proapoptotic function via interaction or modulation of specific proteins. Such evidence is particularly associated with the RTN1-C family members. In order to explore proteins that interact with RTN1-C, the yeast two-hybrid system and regular molecular biological techniques were used to screen the human fetal brain cDNA library. As a result, seven RTN1-C interacting proteins including Homo sapiens mesencephalic astrocyte-derived neurotrophic factor (MANF) were obtained. The interactions between RTN1-C and its interacting proteins were confirmed by β-galactosidase assay and growth test in selective media. Moreover, the MANF/RTN1-C interaction was verified in vitro by glutathione S-transferase pull-down assay and in vivo by immunoprecipitation assay. By immunofluorescence assay, it was found that MANF co-localized with RTN1-C in the ER. Knockdown of RTN1-C reduced the localization of MANF in the ER. These results provide clues to further explore the function of RTN1-C and MANF in neurodegenerative diseases and cancer.

show abstract

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

Cited by 129 publications

References 41 publications

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

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

The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers

Identification of MANF as a protein interacting with RTN1-C

Contact Info

Product

Resources

About