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A Comparative Analysis of the Molecular Features of MANF and CDNF

机译：MANF和CDNF分子特征的比较分析

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摘要

Cerebral dopamine neurotrophic factor (CDNF) is a paralogous protein of mesencephalic astrocyte-derived neurotrophic factor (MANF). Both proteins have been reported to show a common cytoprotective effect on dopaminergic neurons as a secretory protein containing the KDEL-like motif of the ER retrieval signal at the C-terminus, RTDL in MANF and [Q/K]TEL in CDNF among many species, although functions of paralogous proteins tend to differ from each other. In this study, we focused on post-translational regulations of their retention in the endoplasmic reticulum (ER) and secretion and performed comparative experiments on characterization of mouse MANF and mouse CDNF according to our previous report about biosynthesis and secretion of mouse MANF using a NanoLuc system. In this study, co-expression of glucose-regulated protein 78 kDa (GRP78), KDEL receptor 1 or mutant Sar1 into HEK293 cells similarly decreased MANF and CDNF secretion with some degree of variation. Next, we investigated whether CDNF affects the secretion of mouse cysteine-rich with EGF-like domains 2 (CRELD2) because mouse wild-type (wt) MANF but not its KDEL-like motif deleted mutant (ΔCMANF) was found to promote the CRELD2 release from the transfected cells. Co-expressing CRELD2 with wt or ΔC CDNF, we found that CDNF and ΔCMANF hardly elevated the CRELD2 secretion. We then investigated effects of the four or six C-terminal amino acids of MANF and CDNF on the CRELD2 secretion. As a result, co-transfection of mouse CDNF having the mouse MANF-type C-terminal amino acids (CDNFRTDL and CDNFSARTDL) increased the CRELD2 secretion to a small extent, but mouse CDNF having human CDNF-type ones (CDNFKTEL and CDNFHPKTEL) well increased the CRELD2 secretion. On the other hand, the replacement of C-terminal motifs of mouse MANF with those of mouse CDNF (MANFQTEL and MANFYPQTEL) enhanced the CRELD2 secretion, and the mouse MANF having human CDNF-type ones (MANFKTEL and MANFHPKTEL) dramatically potentiated the CRELD2 secretion. These results indicate that the secretion of mouse MANF and mouse CDNF is fundamentally regulated in the same manner and that the variation of four C-terminal amino acids in the MANF and CDNF among species might influence their intracellular functions. This finding could be a hint to identify physiological functions of MANF and CDNF.
机译：脑多巴胺神经营养因子（CDNF）是中脑星形胶质细胞源性神经营养因子（MANF）的旁系蛋白。据报道，这两种蛋白都对多巴胺能神经元具有共同的细胞保护作用，这是一种分泌蛋白，在许多物种中都包含C端ER检索信号的KDEL样基序，MANF中的RTDL和CDNF中的[Q / K] TEL ，尽管旁源蛋白的功能往往彼此不同。在这项研究中，我们专注于翻译后调节其在内质网（ER）中的保留和分泌的功能，并根据我们先前有关使用NanoLuc进行小鼠MANF的生物合成和分泌的报告，对小鼠MANF和小鼠CDNF的特性进行了对比实验。系统。在这项研究中，将葡萄糖调节蛋白78 kDa（GRP78），KDEL受体1或突变型Sar1共表达到HEK293细胞中，同样会在一定程度上降低MANF和CDNF的分泌。接下来，我们研究了CDNF是否会影响具有EGF样域2（CRELD2）的富含小鼠半胱氨酸的分泌，因为发现小鼠野生型（wt）MANF但未发现其KDEL样基序缺失突变体（ΔCMANF）促进了CRELD2从转染的细胞中释放。与wt或ΔCCDNF共表达CRELD2，我们发现CDNF和ΔCMANF几乎不提高CRELD2的分泌。然后，我们研究了MANF和CDNF的4个或6个C末端氨基酸对CRELD2分泌的影响。结果，具有小鼠MANF型C末端氨基酸（CDNFRTDL和CDNFSARTDL）的小鼠CDNF的共转染在一定程度上增加了CRELD2的分泌，但是具有人CDNF型的小鼠CDNF（CDNFKTEL和CDNFHPKTEL）很好增加了CRELD2的分泌。另一方面，用小鼠CDNF（MANFQTEL和MANFYPQTEL）替代小鼠MANF的C末端基序增强了CRELD2的分泌，而具有人CDNF型的小鼠MANF（MANFKTEL和MANFHPKTEL）的小鼠MANF显着增强了CRELD2的分泌。 。这些结果表明，小鼠MANF和小鼠CDNF的分泌从根本上以相同的方式调节，并且MANF和CDNF中物种之间的四个C末端氨基酸的变化可能影响它们的细胞内功能。这一发现可能是鉴定MANF和CDNF的生理功能的提示。

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