A team from Fudan University and EPFL demonstrates that RNAi silencing of intestinal v-ATPase subunits in Caenorhabditis elegans activates a novel Lysosomal Surveillance Response (LySR). LySR is governed by the GATA transcription factor ELT-2 and CBP-1 acetyltransferase, upregulating lysosomal proteases and enhancing proteostasis to extend healthspan.
Key points
Targeted RNAi of intestinal v-ATPase subunits (vha-6, vha-8, vha-14, vha-15, vha-20) in C. elegans triggers LySR and extends lifespan by ~60%.
LySR induction requires CBP-1-mediated H3K27 acetylation and ELT-2 binding to a specific promoter motif, upregulating lysosomal proteases like CPR-5.
Enhanced lysosomal acidification and cathepsin maturation improve proteostasis, clearing aggregates in Alzheimer’s, Huntington’s, and ALS worm models.
Why it matters:
Identifying a conserved lysosome-centered longevity mechanism opens new therapeutic avenues to combat age-related proteotoxic diseases by enhancing cellular clearance pathways.
Q&A
What is the Lysosomal Surveillance Response (LySR)?
Why silence v-ATPase instead of activating it?
How do ELT-2 and CBP-1 collaborate in LySR activation?
What models demonstrate LySR benefits?
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Academy
Understanding Lysosomal Surveillance Response (LySR)
Introduction
As we age, our cells accumulate damaged proteins and waste products. These toxic aggregates impair cellular function and contribute to age-related diseases like Alzheimer’s, Parkinson’s, and Huntington’s. The lysosome, a cellular “recycling center,” breaks down and clears many of these waste materials. Recent research in the model organism Caenorhabditis elegans has uncovered a novel protective pathway called the Lysosomal Surveillance Response (LySR), showing how cells can boost their waste-clearing capacity to extend healthy lifespan.
1. What is the Lysosomal Surveillance Response?
LySR is an adaptive genetic program that cells activate when they detect stress at the intestinal interface. Specifically, when certain proton-pump subunits (called v-ATPase a-subunits) in the worm’s intestinal lining are partially silenced, the animal triggers LySR. This response turns on hundreds of genes related to lysosomes, immune defense, and metabolism. Many of these genes code for cathepsins—enzymes that digest proteins inside lysosomes.
2. Key Players: ELT-2 and CBP-1
- ELT-2: A GATA family transcription factor (a protein that switches genes on). It binds to a 10-base DNA motif found near the start sites of LySR genes.
- CBP-1: The worm equivalent of the human CBP/p300 acetyltransferase. It adds chemical tags (acetyl groups) to histone proteins (H3K27Ac), opening the chromatin structure so ELT-2 can access target genes.
When v-ATPase subunits are silenced, CBP-1 activity increases H3K27 acetylation, ELT-2 binds promoter regions, and robust transcription of lysosomal proteases such as CPR-5 and CPR-8 follows.
3. Boosting Lysosomal Function and Protein Clearance
Under LySR, lysosomal acidification remains intact or even improves, ensuring that digestive enzymes work at optimal pH. Cells show increased maturation of cathepsin L (CPL-1) and higher proteolytic activity. As a result, toxic protein aggregates—hallmarks of neurodegenerative disorders—are cleared more efficiently.
4. Evidence from Worm Models
- Alzheimer’s model: Worms expressing human Aβ1–42 develop paralysis and amyloid deposits. LySR activation nearly eliminates these aggregates and restores movement.
- Huntington’s model: Worms with toxic polyglutamine (polyQ) expansions have fewer huntingtin aggregates under LySR.
- ALS model: Mutant SOD1 aggregates decline dramatically when LySR is engaged.
These results show that LySR provides broad protection against proteotoxic stress.
5. Relevance to Healthy Aging
LySR counters the decline of lysosomal and proteostasis function that naturally occurs with age. By maintaining efficient waste clearance, cells preserve health and delay age-related pathologies. This discovery highlights lysosomes as promising targets for therapies aimed at promoting longevity and combating neurodegeneration.
Conclusion
The Lysosomal Surveillance Response reveals a conserved mechanism to boost cellular cleanup operations and extend healthspan. By understanding and harnessing LySR, we may develop new interventions to keep our cells “clean,” healthy, and youthful.
