RRC ID 59505
Author Hartman JH, Richie CT, Gordon KL, Mello DF, Castillo P, Zhu A, Wang Y, Hoffer BJ, Sherwood DR, Meyer JN, Harvey BK.
Title MANF deletion abrogates early larval Caenorhabditis elegans stress response to tunicamycin and Pseudomonas aeruginosa.
Journal Eur J Cell Biol
Abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) is the only human neurotrophic factor with an evolutionarily-conserved C. elegans homolog, Y54G2A.23 or manf-1. MANF is a small, soluble, endoplasmic-reticulum (ER)-resident protein that is secreted upon ER stress and promotes survival of target cells such as neurons. However, the role of MANF in ER stress and its mechanism of cellular protection are not clear and the function of MANF in C. elegans is only beginning to emerge. In this study, we show that depletion of C. elegans manf-1 causes a slight decrease in lifespan and brood size; furthermore, combined depletion of manf-1 and the IRE-1/XBP-1 ER stress/UPR pathway resulted in sterile animals that did not produce viable progeny. We demonstrate upregulation of markers of ER stress in L1 larval nematodes, as measured by hsp-3 and hsp-4 transcription, upon depletion of manf-1 by RNAi or mutation; however, there was no difference in tunicamycin-induced expression of hsp-3 and hsp-4 between wild-type and MANF-deficient worms. Surprisingly, larval growth arrest observed in wild-type nematodes reared on tunicamycin is completely prevented in the manf-1 (tm3603) mutant. Transcriptional microarray analysis revealed that manf-1 mutant L1 larvae exhibit a novel modulation of innate immunity genes in response to tunicamycin. The hypothesis that manf-1 negatively regulates the innate immunity pathway is supported by our finding that the development of manf-1 mutant larvae compared to wild-type larvae is not inhibited by growth on P. aeruginosa. Together, our data represent the first characterization of C. elegans MANF as a key modulator of organismal ER stress and immunity.
Volume 98(5-8)
Pages 151043
Published 2019-12-1
DOI 10.1016/j.ejcb.2019.05.002
PII S0171-9335(18)30348-0
PMID 31138438
PMC PMC7336501
MeSH Animals Anti-Bacterial Agents / pharmacology* Caenorhabditis elegans / drug effects* Caenorhabditis elegans / genetics* Caenorhabditis elegans / growth & development Caenorhabditis elegans / microbiology Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Endoplasmic Reticulum Stress / drug effects* Immunity, Innate / drug effects Larva / drug effects Larva / immunology Nerve Growth Factors / deficiency* Nerve Growth Factors / genetics* Nerve Growth Factors / metabolism Pseudomonas aeruginosa / growth & development Pseudomonas aeruginosa / metabolism Tunicamycin / pharmacology*
IF 3.024
Times Cited 3
C.elegans tm3603 tm903 tm907