A memory of eS25 loss drives resistance phenotypes.


Journal

Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011

Informations de publication

Date de publication:
27 07 2020
Historique:
accepted: 24 05 2020
revised: 11 05 2020
received: 27 03 2020
pubmed: 29 5 2020
medline: 17 9 2020
entrez: 29 5 2020
Statut: ppublish

Résumé

In order to maintain cellular protein homeostasis, ribosomes are safeguarded against dysregulation by myriad processes. Remarkably, many cell types can withstand genetic lesions of certain ribosomal protein genes, some of which are linked to diverse cellular phenotypes and human disease. Yet the direct and indirect consequences from these lesions are poorly understood. To address this knowledge gap, we studied in vitro and cellular consequences that follow genetic knockout of the ribosomal proteins RPS25 or RACK1 in a human cell line, as both proteins are implicated in direct translational control. Prompted by the unexpected detection of an off-target ribosome alteration in the RPS25 knockout, we closely interrogated cellular phenotypes. We found that multiple RPS25 knockout clones display viral- and toxin-resistance phenotypes that cannot be rescued by functional cDNA expression, suggesting that RPS25 loss elicits a cell state transition. We characterized this state and found that it underlies pleiotropic phenotypes and has a common rewiring of gene expression. Rescuing RPS25 expression by genomic locus repair failed to correct for the phenotypic and expression hysteresis. Our findings illustrate how the elasticity of cells to a ribosome perturbation can drive specific phenotypic outcomes that are indirectly linked to translation and suggests caution in the interpretation of ribosomal protein gene mutation data.

Identifiants

pubmed: 32463448
pii: 5848244
doi: 10.1093/nar/gkaa444
pmc: PMC7367175
doi:

Substances chimiques

Neoplasm Proteins 0
RACK1 protein, human 0
RPS25 protein, human 0
Receptors for Activated C Kinase 0
Ribosomal Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

7279-7297

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM113078
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI099506
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI141970
Pays : United States
Organisme : NIH HHS
ID : S10 OD020141
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000044
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG064690
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI140186
Pays : United States
Organisme : NIDDK NIH HHS
ID : F31 DK112570
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR026780
Pays : United States

Informations de copyright

© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.

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Auteurs

Alex G Johnson (AG)

Department of Structural Biology, Stanford University, Stanford, CA 94305, USA.
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.

Ryan A Flynn (RA)

Department of Chemistry, Stanford University, Stanford, CA 94305, USA.

Christopher P Lapointe (CP)

Department of Structural Biology, Stanford University, Stanford, CA 94305, USA.

Yaw Shin Ooi (YS)

Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA.

Michael L Zhao (ML)

Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.

Christopher M Richards (CM)

Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA.

Wenjie Qiao (W)

Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA.

Shizuka B Yamada (SB)

Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Julien Couthouis (J)

Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Aaron D Gitler (AD)

Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Jan E Carette (JE)

Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA.

Joseph D Puglisi (JD)

Department of Structural Biology, Stanford University, Stanford, CA 94305, USA.

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