Graded Proteasome Dysfunction in Caenorhabditis elegans Activates an Adaptive Response Involving the Conserved SKN-1 and ELT-2 Transcription Factors and the Autophagy-Lysosome Pathway

摘要

The maintenance of cellular proteins in a biologically active and structurally stable state is a vital endeavor involving multiple cellular pathways. One such pathway is the ubiquitin-proteasome system that represents a major route for protein degradation, and reductions in this pathway usually have adverse effects on the health of cells and tissues. Here, we demonstrate that loss-of-function mutants of the Caenorhabditis elegans proteasome subunit, RPN-10, exhibit moderate proteasome dysfunction and unexpectedly develop both increased longevity and enhanced resistance to multiple threats to the proteome, including heat, oxidative stress, and the presence of aggregation prone proteins. The rpn-10 mutant animals survive through the activation of compensatory mechanisms regulated by the conserved SKN-1/Nrf2 and ELT-2/GATA transcription factors that mediate the increased expression of genes encoding proteasome subunits as well as those mediating oxidative- and heat-stress responses. Additionally, we find that the rpn-10 mutant also shows enhanced activity of the autophagy-lysosome pathway as evidenced by increased expression of the multiple autophagy genes including atg-16 . 2 , lgg-1 , and bec-1 , and also by an increase in GFP::LGG-1 puncta. Consistent with a critical role for this pathway, the enhanced resistance of the rpn-10 mutant to aggregation prone proteins depends on autophagy genes atg-13 , atg-16 . 2 , and prmt-1 . Furthermore, the rpn-10 mutant is particularly sensitive to the inhibition of lysosome activity via either RNAi or chemical means. We also find that the rpn-10 mutant shows a reduction in the numbers of intestinal lysosomes, and that the elt-2 gene also plays a novel and vital role in controlling the production of functional lysosomes by the intestine. Overall, these experiments suggest that moderate proteasome dysfunction could be leveraged to improve protein homeostasis and organismal health and longevity, and that the rpn-10 mutant provides a unique platform to explore these possibilities. Author Summary Proteins are complex molecules assembled from individual amino acids that are linked head to tail in a linear chain. Once assembled, the proteins play vital roles in the structure and function of every cell in the body. However, for these proteins to work properly, they must be assembled correctly and resist damage from stresses originating either from inside the body or from the environment. One way that proteins are safeguarded is through the careful removal and destruction of damaged or unwanted proteins via a molecular machine termed the proteasome, which cleaves the protein chain and releases the individual amino acids back into the cell. Usually a loss of proteasome activity leads to a loss of the quality control mechanisms for cellular proteins and can contribute to aging or the development of diseases, such as Alzheimer’s disease. Here we find that when proteasome activity is only partially reduced, several other protein quality control mechanisms are activated, and this actually leads to a net increase in protein quality. This effect could be utilized to help prevent diseases and aspects of aging caused by the accumulation of damaged proteins.