MESSAI.iO

AI summary

75% confidence

In aging Drosophila, the transcription factor CREB is activated by JNK signaling in the gut and subsequently suppresses the expression of PGRP-SC2. This suppression leads to altered microbiota composition characterized by a decreased Firmicutes/Bacteroidetes ratio and contributes to immune senescence and lifespan shortening.

Generated by MESSAI extraction pipeline · review against source PDF

Extraction

Reported parameters

55 extracted values

View extracted values

No 3D model is mapped to this paper yet. Parameter ranges above still place reported values on the literature distribution.

Abstract

Abstract The maintenance of immune homeostasis is critical for tissue health and longevity, yet the regulatory mechanisms linking immune modulation to aging remain poorly understood. Here we found that the transcription factor cAMP response element-binding protein (CREB), activated by JNK signaling in aging guts, transcriptionally suppresses peptidoglycan recognition protein SC2( PGRP-SC2) —a homolog of anti-inflammatory PGLYRP1–4 with amidase activity. 16S rRNA sequencing revealed that CREB modulates not only microbial load but also microbiota composition. Elevated CREB activity decreased the Firmicutes/Bacteroidetes (F/B) ratio—a hallmark of age-associated dysbiosis in animals. Genetic enhancement of PGRP-SC2 rescues age-related gut hyperplasia, microbiota imbalance, and lifespan shortening induced by overactivation of CREB or its coactivator CRTC. Notably, CREB’s regulation of PGRP-SC2 operates independently of canonical immune pathways such as Imd/Relish, revealing a previously unrecognized layer of immune modulation. Our findings establish CREB as a central player in age-associated immune dysregulation and propose targeting the CREB-PGRP-SC2 axis as a potential therapeutic strategy for mitigating gut aging and its systemic consequences.

Key findings

  • CREB transcriptionally suppresses peptidoglycan recognition protein SC2 (PGRP-SC2) in aging guts via JNK signaling activation.
  • Elevated CREB activity decreases the Firmicutes/Bacteroidetes ratio, a hallmark of age-associated gut dysbiosis.
  • Genetic enhancement of PGRP-SC2 rescues age-related gut hyperplasia, microbiota imbalance, and lifespan shortening caused by CREB overactivation.

Keywords

CREBImmune systemCell biologyTranscription factorDysbiosisSignal transduction

Identifiers

DOI
10.1038/s41420-026-02955-w
Journal
Cell Death Discovery
Year
2026