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.
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Data availability
The 16S rRNA gene sequence data have been deposited in China National Center for Bioinformation (CNCB) (GSA: CRA018399 and CRA030538) with the link: https://ngdc.cncb.ac.cn/gsa/. All study data are included in the article and supporting information.
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Acknowledgements
We thank Bloomington Drosophila Stock Center, Vienna Drosophila Stock Center, Tsinghua Fly Center and Dr. Lei Xue and Dr. Heinrich Jasper for stocks and reagents.
Funding
This work was supported by a National Key Research and Development Project [2018YFA0107100], National Natural Science Foundation of China [grant no. 31871371 and 32071147] and Tongji University Basic Scientific Research-Interdisciplinary Fund [grant no. 2000123424] to H.D.
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HD and SW conceived and designed the study. HD prepared the first draft of the paper. SW, BQ, PM, YZ, YY, SC contributed to the experimental work. SW conducted the statistical analysis of the data.
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Wang, S., Qi, B., Ma, P. et al. CREB suppresses PGRP-SC2 to drive age-related immune senescence and gut dysbiosis in Drosophila. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-02955-w
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DOI: https://doi.org/10.1038/s41420-026-02955-w
