Spatial regulation of proteostasis during aging in Caenorhabditis elegans
Louis Lapierre
Université de Moncton
Moncton, NB, Canada
Summary:
Protein homeostasis (proteostasis) is essential for maintaining cellular function and preventing the accumulation of damaged and misfolded proteins during aging. Although proteostasis is traditionally viewed as a balance between protein synthesis, folding, and degradation, emerging evidence indicates that the spatial organization and partitioning of proteins and proteostatic machinery across subcellular compartments and tissues are equally important determinants of proteome integrity. Using Caenorhabditis elegans, our work investigates how spatially regulated proteostatic mechanisms contribute to protein quality control and longevity.
By examining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we uncovered a role for subcellular protein partitioning in autophagic flux and identified lipid droplets as an unexpected proteostatic compartment. Unbiased genome-wide RNAi screening for SQST-1/SQSTM1 revealed that lipid droplet-associated proteins modulate proteostasis. Increasing intestinal lipid droplets through inhibition of atgl-1/ATGL promoted autophagy, facilitated the accumulation and handling of ubiquitinated proteins, and extended lifespan. Conversely, reducing lipid droplets exacerbated proteostatic collapse and shortened the lifespan of long-lived daf-2 animals, establishing lipid droplets as important spatial mediators of proteostasis and longevity.
We also investigated how proteostatic burden is distributed across tissues during aging. Validation of commonly used tissue-specific RNAi systems revealed substantial and temperature-dependent differences in RNAi sensitivity among rde-1 and sid-1 mutant backgrounds, highlighting important considerations for interpreting tissue-specific RNAi studies. Using validated systems, we found that proteasomal burden differs markedly between the germline and soma, with age-dependent accumulation of vitellogenin proteins contributing substantially to polyubiquitinated protein levels in the gonad. Unexpectedly, we further found that the polyubiquitin gene ubq-1 is required for transcription of highly expressed genes, including vitellogenins, revealing a broader role for ubiquitin beyond protein degradation.
Taken together, these findings demonstrate that proteostasis during aging is regulated across multiple spatial scales—from subcellular compartments to individual tissues—and that these spatially organized mechanisms are tightly linked to organismal longevity. Our work highlights protein partitioning, lipid droplets, autophagy, proteasomal function, and tissue-specific proteostatic burden as interconnected determinants of proteome maintenance during aging, providing new avenues for understanding and modulating age-associated proteostatic decline.
By examining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we uncovered a role for subcellular protein partitioning in autophagic flux and identified lipid droplets as an unexpected proteostatic compartment. Unbiased genome-wide RNAi screening for SQST-1/SQSTM1 revealed that lipid droplet-associated proteins modulate proteostasis. Increasing intestinal lipid droplets through inhibition of atgl-1/ATGL promoted autophagy, facilitated the accumulation and handling of ubiquitinated proteins, and extended lifespan. Conversely, reducing lipid droplets exacerbated proteostatic collapse and shortened the lifespan of long-lived daf-2 animals, establishing lipid droplets as important spatial mediators of proteostasis and longevity.
We also investigated how proteostatic burden is distributed across tissues during aging. Validation of commonly used tissue-specific RNAi systems revealed substantial and temperature-dependent differences in RNAi sensitivity among rde-1 and sid-1 mutant backgrounds, highlighting important considerations for interpreting tissue-specific RNAi studies. Using validated systems, we found that proteasomal burden differs markedly between the germline and soma, with age-dependent accumulation of vitellogenin proteins contributing substantially to polyubiquitinated protein levels in the gonad. Unexpectedly, we further found that the polyubiquitin gene ubq-1 is required for transcription of highly expressed genes, including vitellogenins, revealing a broader role for ubiquitin beyond protein degradation.
Taken together, these findings demonstrate that proteostasis during aging is regulated across multiple spatial scales—from subcellular compartments to individual tissues—and that these spatially organized mechanisms are tightly linked to organismal longevity. Our work highlights protein partitioning, lipid droplets, autophagy, proteasomal function, and tissue-specific proteostatic burden as interconnected determinants of proteome maintenance during aging, providing new avenues for understanding and modulating age-associated proteostatic decline.
Invité par Audrey Esclatine (audrey.esclatine@i2bc.paris-saclay.fr)