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Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation

Aging is associated with declining protein homeostasis. Here, using a chemical mutagenesis screen for lifespan extension in C. elegans, the authors report that inhibition of the integrated stress response enhances longevity and protein homeostasis in a manner dependent on kin-35, without reducing protein synthesis.

Maxime J. Derisbourg
Laura E. Wester
Martin S. Denzel
ResearchOpen Access15 Mar 2021
Nature Communications

Volume: 12, P: 1-14
Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1

The glutamine fructose-6-phosphate amidotransferase 1 (GFAT-1) is the rate-limiting enzyme in the hexosamine pathway producing uridine 5’-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc), an essential glycosylation precursor. Here, the authors dissect the mechanisms of GFAT-1 regulation by protein kinase A (PKA)-mediated phosphorylation.

Sabine Ruegenberg
Felix A. M. C. Mayr
Martin S. Denzel
ResearchOpen Access12 Apr 2021
Nature Communications

Volume: 12, P: 1-14
Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis

Mutations in the hexosamine pathway key enzyme glutamine fructose-6-phosphate amidotransferase (GFAT-1) improve protein quality control and extend C. elegans lifespan. Here the authors present the crystal structures of full-length human GFAT-1 alone and with bound ligands and perform activity assays, which show that gain-of-function in the longevity-associated G451E variant is caused by a loss of feedback regulation.

Sabine Ruegenberg
Moritz Horn
Martin S. Denzel
ResearchOpen Access04 Feb 2020
Nature Communications

Volume: 11, P: 1-16
Small-molecule inhibitors of human mitochondrial DNA transcription

Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.

Nina A. Bonekamp
Bradley Peter
Nils-Göran Larsson
Research16 Dec 2020
Nature

Volume: 588, P: 712-716
Modulating the integrated stress response to slow aging and ameliorate age-related pathology

The integrated stress response governs adaptive reprogramming of protein synthesis following external or internal signals. The authors discuss its role in aging and longevity, and highlight strategies to enhance health and resilience.

Maxime J. Derisbourg
Matías D. Hartman
Martin S. Denzel
Reviews13 Sept 2021
Nature Aging

Volume: 1, P: 760-768
Nuclear signalling by tumour-associated antigen EpCAM

The intracellular fragment of the adhesion molecule EpCAM, which is generated by the proteases TACE and presenilin-2, increases cell proliferation and acts in a complex with β-catenin and Lef-1 to regulate gene expression.

Dorothea Maetzel
Sabine Denzel
Olivier Gires
Research11 Jan 2009
Nature Cell Biology

Volume: 11, P: 162-171
Bortezomib resistance mutations in PSMB5 determine response to second-generation proteasome inhibitors in multiple myeloma

Kira Allmeroth
Moritz Horn
Martin S. Denzel
ResearchOpen Access20 Jul 2020
Leukemia

Volume: 35, P: 887-892
fMRI Revealed Reduced Amygdala Activation after Nx4 in Mildly to Moderately Stressed Healthy Volunteers in a Randomized, Placebo-Controlled, Cross-Over Trial

Luisa Herrmann
Petya Vicheva
Martin Walter
ResearchOpen Access02 Mar 2020
Scientific Reports

Volume: 10, P: 1-14

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