Proteomics

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The tumor suppressor Fhit in complex with the alarmone Ap3A binds to the ribosome and impedes translation

ABSTRACT: Upon cellular stress, the concentration of the alarmone diadenosine triphosphate (Ap3A) increases and is thought to trigger downstream adaptive processes. The known Ap3A-hydrolase fragile histidine triad (Fhit) is known to form a complex with Ap3A. The molecular mechanism of Fhit-Ap3A signaling is however unknown. In this study, by synthesizing a covalent Fhit-Ap3A complex we have elucidated the Ap3A-dependent cellular interactome by mass spectrometry-based proteome profiling. Interestingly, we found a significant enrichment of proteins involved in translation. We then show that Fhit translocates from the nucleolus into the cytosol upon stress to form a Fhit-Ap3A complex which impedes translation both in vitro and in vivo in an Ap3A dependent manner resulting in reduced cell viability. Overall, our findings provide a mechanistic model by which the tumor suppressor Fhit collaborates with the alarmone Ap3A to regulate cellular proliferation.

INSTRUMENT(S): Orbitrap Fusion, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Florian Stengel  

LAB HEAD: Andreas Marx

PROVIDER: PXD029645 | Pride | 2022-12-20

REPOSITORIES: Pride

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DH_ribo_fhit_exp3DB.fasta Fasta
F2105_jansenja_079.raw Raw
F2105_jansenja_080.raw Raw
F2105_jansenja_081.raw Raw
F2105_jansenja_082.raw Raw
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Publications

Chemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap<sub>3</sub>A Elucidates Its Inhibitory Action on Translation.

Herzog Doreen D   Jansen Jasmin J   Mißun Maite M   Diederichs Kay K   Stengel Florian F   Marx Andreas A  

Journal of the American Chemical Society 20220506 19

The tumor suppressor protein <i>fragile histidine triad</i> (Fhit) is known to be associated with genomic instability and apoptosis. The tumor-suppressive function of Fhit depends on the interaction with the alarmone diadenosine triphosphate (Ap<sub>3</sub>A), a noncanonical nucleotide whose concentration increases upon cellular stress. How the Fhit-Ap<sub>3</sub>A complex exerts its signaling function is unknown. Here, guided by a chemical proteomics approach employing a synthetic stable Fhit-A  ...[more]

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