Recombinant Human Mesencephalic astrocyte-derived neurotrophic factor protein (MANF)

Function

Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain (PubMed:12794311). Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra (By similarity). Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons (By similarity). Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death (PubMed:18561914, PubMed:22637475, PubMed:29497057, PubMed:36739529). Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions (PubMed:22637475). Stabilizes HSPA5/BiP in its substrate-bound ADP state, which facilitates HSPA5/BiP incorporation into chaperone-client complexes during endoplasmic reticulum stress, its interaction with HSPA5/BiP inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange (By similarity). As a result acts as a repressor of the unfolded protein response (UPR) pathway (By similarity). Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia (PubMed:22637475). Following secretion by the ER/SR, directly binds to 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells (PubMed:29497057). Sulfatide binding promotes its cellular uptake by endocytosis, and is required for its role in alleviating ER stress and cell toxicity under hypoxic and ER stress conditions (PubMed:29497057). Essential for embryonic lung development (By similarity). Required for the correct postnatal temporal and structural development of splenic white pulp (By similarity). Required for the repair-associated myeloid response in skeletal muscle, acts as a regulator of phenotypic transition towards prorepair macrophages in response to muscle injury and as a result limits excessive proinflammatory signaling (By similarity). Represses RELA expression and therefore NF-kB signaling in the myocardium, as a result limits macrophage infiltration of injured tissue and M1 macrophage differentiation in response to myocardial injury (By similarity). Required for endochondral ossification in long bones and the skull during postnatal development (By similarity)

Subcellular Location

Secreted; Endoplasmic reticulum lumen; Sarcoplasmic reticulum lumen

Disease Association

Diabetes, deafness, developmental delay, and short stature syndrome (DDDS) : An autosomal recessive, multisystem disorder characterized by childhood-onset non-autoimmune diabetes mellitus, short stature, bilateral sensorineural deafness, developmental delay, mildly impaired intellectual development, and microcephaly. [The disease is caused by variants affecting the gene represented in this entry]

Subunit

Interacts directly (via SAP domain) with HSPA5/BiP; the interaction inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange (PubMed:22637475). Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4 (By similarity). Interacts (via C-terminus) with ERN1 (via luminal domain); the interaction is decreased in the presence of increasing concentrations of Ca(2+) (PubMed:36739529)

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• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Muzny D.M. et al. The DNA sequence, annotation and analysis of human chromosome 3. — Nature (2006)
• Gevaert K. et al. Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. — Nat. Biotechnol. (2003)
• Petrova P. et al. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. — J. Mol. Neurosci. (2003)
• Brill L.M. et al. Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. — Anal. Chem. (2004)
• Apostolou A. et al. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. — Exp. Cell Res. (2008)