person: Hung-Jen Shih

Vanderbilt University Medical Center; Nashville TN, United States of America

paper:

Shih, Hung-jen et al. (2021) International Worm Meeting "Collagen gene variants, endoplasmic reticulum homeostasis, and aging"

Flibotte, Stephane, Shih, Hung-Jen, Hu, Patrick, Allen, Matthew, Cha, Jeeyeon, Bastarache, Lisa

[International Worm Meeting, 2021]

One third of all proteins are cotranslationally translocated into the endoplasmic reticulum (ER) during their biogenesis. A conserved homeostatic mechanism known as the ER unfolded protein response (UPR) has evolved to ensure protein folding homeostasis (proteostasis) in the ER lumen by tuning ER chaperone and protein degradative capacity to accommodate changes in unfolded protein load. Failure of the ER UPR can lead to protein misfolding and aggregation, a condition known as "ER stress" which is associated with common human diseases associated with aging such as Alzheimer's disease, Parkinson's disease, and diabetes. Therefore, insights into the molecular underpinnings of the ER UPR will likely lead to improved strategies to promote healthy aging through the maintenance of ER homeostasis. In previous studies we discovered that trap-1 null mutants exhibit constitutive expression of the hsp-4::GFP ER UPR reporter. To gain insight into how TRAP-1 contributes to ER homeostasis, we performed a genetic screen for modifiers of the trap-1 mutant phenotype. We mutagenized trap-1;hsp-4::GFP worms and screened for F2 progeny with either increased or decreased GFP expression. One strain with increased GFP expression harbored a causal missense mutation in the col-75 collagen gene (dp691). A col-75 nonsense allele does not induce hsp-4::GFP expression, indicating that hsp-4::GFP induction is not due to loss of col-75 activity. Surprisingly, while col-75 is expressed primarily in the excretory cell, socket glia, and pharyngeal neurons, it induces hsp-4::GFP expression non-autonomously and specifically in intestine and spermatheca. Intriguingly, although germline missense mutations in human collagen genes that induce chronic ER stress typically cause disease, col-75(dp691) animals are healthy and retain wild-type levels of resistance to the ER stress inducer tunicamycin. A phenome-wide association study (PheWAS) of all common human COL missense alleles in the BioVU de-identified electronic health record-linked DNA biobank captured on the Illumina Exome BeadChip array revealed the association of several COL gene variants with protection from diagnoses of aging-related diseases such as heart failure, cancer, kidney disease, spinal stenosis, and inflammatory bowel disease. We hypothesize that collagen gene missense mutations that cause constitutive ER UPR induction have context-dependent effects on cellular and organismal fitness and may contribute to human health through constitutive ER UPR induction.

paper:

Shih, Hung-Jen et al. (2013) International Worm Meeting "EGL-8, a phospholipase C beta homolog, is a novel regulator of dauer arrest."

Dumas, Kathleen J., Moerman, Donald G., Flibotte, Stephane, Shih, Hung-Jen, Polzin, Andrew, Hu, Patrick J.

[International Worm Meeting, 2013]

We have identified the phospholipase C beta (PLCb) homolog EGL-8 as a novel regulator of dauer arrest in C. elegans. To identify new regulators of the FoxO transcription factor DAF-16, we performed a genetic screen for suppressors of the eak-7;akt-1 dauer-constitutive phenotype (seak mutants). Three independent mutants harbored distinct mutations in egl-8, which encodes the sole C. elegans PLCb family member. egl-8(dp14), which is a nonsense mutation in the N-terminal pleckstrin homology domain, suppresses eak-7;akt-1 dauer arrest, as does the independently isolated null allele egl-8(sa47). Therefore, egl-8/PLCb is a bonafide seak gene. egl-8(sa47) suppresses the dauer-constitutive phenotypes of the insulin-like pathway mutants daf-2(e1368) and akt-1(ok525) but does not influence the dauer-constitutive phenotype of the TGFb-like pathway mutant daf-1(m40), suggesting that EGL-8/PLCb specifically influences dauer regulation by DAF-2 insulin-like signaling. Our findings suggest that EGL-8/PLCb may be a novel regulator of DAF-16/FoxO activity.

strain: CF980

Caenorhabditis elegans

strain: CF978

Caenorhabditis elegans

strain: PS8438

Caenorhabditis elegans

strain: ZM6523

Caenorhabditis elegans

strain: ZM9028

Caenorhabditis elegans

strain: ZM8561

Caenorhabditis elegans

strain: ZM8988

Caenorhabditis elegans