LARP1 senses free ribosomes to coordinate supply and demand of ribosomal proteins.

Journal

bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187

Informations de publication

Date de publication:
02 Nov 2023
Historique:
pubmed: 14 11 2023
medline: 14 11 2023
entrez: 14 11 2023
Statut: epublish

Résumé

Terminal oligopyrimidine motif-containing mRNAs (TOPs) encode all ribosomal proteins in mammals and are regulated to tune ribosome synthesis to cell state. Previous studies implicate LARP1 in 40S- or 80S-ribosome complexes that repress and stabilize TOPs. However, a mechanistic understanding of how LARP1 and TOPs interact with these complexes to coordinate TOP outcomes is lacking. Here, we show that LARP1 senses the cellular supply of ribosomes by directly binding non-translating ribosomal subunits. Cryo-EM structures reveal a previously uncharacterized domain of LARP1 bound to and occluding the 40S mRNA channel. Free cytosolic ribosomes induce sequestration of TOPs in repressed 80S-LARP1-TOP complexes independent of alterations in mTOR signaling. Together, this work demonstrates a general ribosome-sensing function of LARP1 that allows it to tune ribosome protein synthesis to cellular demand.

Identifiants

DOI: 10.1101/2023.11.01.565189 PMID: 37961604 PMC: PMC10635049
pubmed: 37961604
doi: 10.1101/2023.11.01.565189
pmc: PMC10635049
pii:
doi:

Types de publication

Preprint

Langues

eng

Subventions

Organisme : NCI NIH HHS
ID : F30 CA260910
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG010538
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM136577
Pays : United States

Déclaration de conflit d'intérêts

Competing interests RG is on the scientific advisory board of Alltrna, Initial Therapeutics and Arrakis Pharmaceuticals and serves as a consultant for Vertex Pharmaceuticals, Brystol-Myers Squibb (Celgene), Monta Rosa Therapeutics, and Flagship Pioneering. RG previously served on the scientific advisory board at Moderna. WT has two patents (8,748,091 and 8,394,584) licensed to ONT and received reimbursement for travel, accommodation, and/or conference fees to speak at events organized by ONT.

Auteurs

James A Saba (JA)

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
These authors contributed equally.
ORCID: 0000-0003-3453-8151

Zixuan Huang (Z)

Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Dong'an Road 131, 200032, Shanghai, China.
These authors contributed equally.

Kate L Schole (KL)

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0003-3737-6792

Xianwen Ye (X)

Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Dong'an Road 131, 200032, Shanghai, China.

Shrey D Bhatt (SD)

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Yi Li (Y)

Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Dong'an Road 131, 200032, Shanghai, China.

Winston Timp (W)

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0003-2083-6027

Jingdong Cheng (J)

Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Dong'an Road 131, 200032, Shanghai, China.

Rachel Green (R)

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Classifications MeSH