bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.11.10.765553

The KAT2 Acetyltransferase PCAF-1 Couples Stress-Responsive Transcription to Proteostasis and Longevity

Sharma, A.·Nisaa, K.·Blanco-Rodriguez, L.·Tachiki, J.·Dinneen, E.·To, M. H.·Silva-Garcia, C. G.
View original source ↗Export metadata ↓

Abstract

Aging erodes the capacity of cells to sense stress and maintain a functional proteome. Lysine acetyltransferases can link stress signals to gene expression, but whether boosting the activity of a single acetyltransferase can enhance stress responses to protect the aging proteome and extend healthspan remains unknown. Here we show that increasing the dosage of PCAF-1, the sole KAT2 family acetyltransferase in Caenorhabditis elegans, is sufficient to extend lifespan, preserve healthspan, and reprogram stress-responsive transcription. This program is conserved; mammalian orthologs of PCAF-1-induced genes are enriched among transcripts that decline upon KAT2A and KAT2B depletion. PCAF-1 strengthens inducible stress responses, attenuates the age-dependent decline in proteasomal degradation, and limits protein aggregation in C. elegans models of human neurodegenerative diseases, while preserving motility and survival. Mechanistically, PCAF-1 drives DAF-16/FOXO activation, and DAF-16 is required for both PCAF-1-dependent longevity and for protection against polyglutamine aggregation. These findings reveal a previously unrecognized mechanism by which KAT2 acetyltransferases promote longevity, positioning KAT2s as potential tunable regulators of proteostasis and healthspan during aging.

Explore related subjects

molecular biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Sharma, A., Nisaa, K., Blanco-Rodriguez, L., Tachiki, J., Dinneen, E., To, M. H., Silva-Garcia, C. G.. 2026-11-12. The KAT2 Acetyltransferase PCAF-1 Couples Stress-Responsive Transcription to Proteostasis and Longevity. https://doi.org/10.64898/2026.11.10.765553

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Engineered Miniature ParTasR Enables Efficient PAMless Genome Editing

TIGR-Tas system holds great promise for genome-engineering applications owing to its compact size and PAMless targeting capability. However, its low editing efficiency in mammalian cells severely limits its broader utility. Here, we engineered a highly active variant of ParTasR, termed eTasR, through structure-guided rational design of ParTasR combined with fusion to the exonuclease TREX2. eTasR increased mammalian editing efficiency from the original 4.29% to 48.94% with an average 26.52-fold increase, significantly surpassing the efficiency of SpRY, a reported version of PAM-free nuclease. More importantly, single-AAV delivery enabled efficient Hpd disruption in vivo, resulting in robust phenotypic rescue. Thus, eTasR provides a compact, PAMless and highly efficient platform for genome editing and therapeutic applications.

molecular biology↗
bioRxiv2026

Enhancing pancreatic islet cell survival via NMDAR antagonist-driven ROR1 activation as revealed by phosphoproteomics

NMDA receptors (NMDARs) control function and survival not only of neurons, but also of insulin-producing pancreatic beta cells. Since insufficient insulin secretion and beta cell death are key events during diabetes development, targeting NMDARs offers a therapeutic approach. Specifically, the NMDAR antagonist dextrorphan (DXO) increases glucose-stimulated insulin secretion in clinical trials. Furthermore, treatment with DXO or optimized DXO derivatives prevents pancreatic islet cell death upon diabetogenic insults. Nonetheless, the signaling pathways induced by NMDAR inhibition are poorly understood. Here, we use complementary approaches, phosphoproteomics and tyrosine kinase profiling, to demonstrate that DXO and its derivatives rapidly regulate multiple intracellular signaling clusters, including mTOR and ERK signaling, in pancreatic islets. Notably, mTOR inhibition, but not ERK inhibition, is sufficient to negate DXO's protective effects. Further, we show that activation of Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) is a universal event upon NMDAR inhibition in islets. Simultaneous knockdown of Ror1/ROR1 and its paralogue Ror2/ROR2 compromises the viability of both mouse and human islets, highlighting the ROR1/2 signaling axis as a promising avenue for enhancing beta cell survival.

molecular biology↗
bioRxiv2026

An ssRNA Phage Single-gene Lysis Protein Targeting MraY Reveals Convergent Evolution Across the RNA-DNA Phage Boundary

Small lytic phages of the ssRNA Leviviricetes and ssDNA Microviricetes achieve host lysis by expression of a single protein, designated as an Sgl protein. Four ssRNA Sgls have been shown to inhibit steps in peptidoglycan biosynthesis: three target MurJ, the Lipid II flippase, and one targets MurA, the committed step of the pathway. A fifth Sgl, the E protein of the canonical ssDNA microvirus {varphi}X174, inhibits MraY, which catalyzes the synthesis of the first lipid-linked intermediate. This inhibition requires SlyD, a cytoplasmic FKBP-type peptidyl-prolyl cis-trans isomerase. The Sgl of the Caulobacter ssRNA phage {varphi}Cb5 (Cebevirus halophobicum) has not been characterized. Here, we present physiological evidence that Sgl{varphi}Cb5 targets MraY. Moreover, we show that, despite the absence of detectable sequence similarity, Sgl{varphi}Cb5 shares several features with the {varphi}X174 E protein, including the distribution of hydrophobic and charged residues, a proposed N-out, C-in membrane topology, and retention of lytic activity in an Sgl{varphi}Cb5 -LacZ fusion. Furthermore, expression of the Caulobacter cytoplasmic FKBP-type peptidyl-prolyl cis-trans isomerase CC2799 enhances Sgl{varphi}Cb5 -mediated lysis in E. coli. These parallels between Sgl function in a DNA phage and an RNA phage either represent remarkably consonant convergent evolution or some evolutionary cross-over event for which there is currently no precedent.

molecular biology↗