Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster

PLoS One. 2016 Mar 14;11(3):e0151550. doi: 10.1371/journal.pone.0151550. eCollection 2016.


Disturbances in the homeostasis of endoplasmic reticulum (ER) referred to as ER stress is involved in a variety of human diseases. ER stress activates unfolded protein response (UPR), a cellular mechanism the purpose of which is to restore ER homeostasis. Previous studies show that Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is an important novel component in the regulation of UPR. In vertebrates, MANF is upregulated by ER stress and protects cells against ER stress-induced cell death. Biochemical studies have revealed an interaction between mammalian MANF and GRP78, the major ER chaperone promoting protein folding. In this study we discovered that the upregulation of MANF expression in response to drug-induced ER stress is conserved between Drosophila and mammals. Additionally, by using a genetic in vivo approach we found genetic interactions between Drosophila Manf and genes encoding for Drosophila homologues of GRP78, PERK and XBP1, the key components of UPR. Our data suggest a role for Manf in the regulation of Drosophila UPR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / genetics
  • Epistasis, Genetic
  • Gene Knockdown Techniques
  • Genes, Insect
  • Genetic Complementation Test
  • Models, Biological
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Phenotype
  • RNA Splicing / genetics
  • Unfolded Protein Response / genetics*
  • Up-Regulation / genetics


  • Drosophila Proteins
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • MANF protein, Drosophila
  • Nerve Growth Factors

Grant support

RL was supported by Viikki Doctoral Programme in Molecular Biosciences (http://www.helsinki.fi/vgsb/), The Finnish Parkinson Foundation (http://www.parkinsonsaatio.fi/), The Ella and Georg Ehrnrooth Foundation (http://www.ellageorg.fi/), and The University of Helsinki Funds, and Alfred Kordelin Foundation (http://www.kordelin.fi/). PL was supported by The Academy of Finland (grant No. 139910; http://www.aka.fi/en-GB/A/). MP was supported by Estonian Research Council (grant No. IUT19-18, http://www.etag.ee/en/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.