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IRE-1 endoribonuclease activity declines early in C. elegans adulthood and is not rescued by reduced reproduction

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Peer-reviewed

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Authors

De-Souza, Evandro A. 
Cummins, Nadia 
Taylor, Rebecca C. 

Abstract

The proteome of a cell helps to define its functional specialization. Most proteins must be translated and properly folded to ensure their biological function, but with aging, animals lose their ability to maintain a correctly folded proteome. This leads to the accumulation of protein aggregates, decreased stress resistance, and the onset of age-related disorders. The unfolded protein response of the endoplasmic reticulum (UPRER) is a central protein quality control mechanism, the function of which is known to decline with age. Here, we show that age-related UPRER decline in Caenorhabditis elegans occurs at the onset of the reproductive period and is caused by a failure in IRE-1 endoribonuclease activities, affecting both the splicing of xbp-1 mRNA and regulated Ire1 dependent decay (RIDD) activity. Animals with a defect in germline development, previously shown to rescue the transcriptional activity of other stress responses during aging, do not show restored UPRER activation with age. This underlines the mechanistic difference between age-associated loss of UPRER activation and that of other stress responses in this system, and uncouples reproductive status from the activity of somatic maintenance pathways. These observations may aid in the development of strategies that aim to overcome the proteostasis decline observed with aging.

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Peer reviewed: True


Acknowledgements: We are grateful to the MRC LMB microscopy facility and media center for expertise and assistance. Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). IXA4 was a kind gift from R. Luke Wiseman (The Scripps Research Institute).

Keywords

Aging, UPR, unfolded protein response, proteostasis, cell stress, stress response, C. elegans, aging, IRE1

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Publisher

Frontiers Media S.A.