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

James A Saba; Zixuan Huang; Kate L Schole; Xianwen Ye; Shrey D Bhatt; Yi Li; Winston Timp; Jingdong Cheng; Rachel Green

doi:10.1101/2023.11.01.565189

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

bioRxiv [Preprint]. 2023 Nov 2:2023.11.01.565189. doi: 10.1101/2023.11.01.565189.

Authors

James A Saba^{1

2

3}, Zixuan Huang^{4

3}, Kate L Schole^{1

2}, Xianwen Ye⁴, Shrey D Bhatt^{1

2}, Yi Li⁴, Winston Timp^{1

5}, Jingdong Cheng⁴, Rachel Green^{1

2}

Affiliations

¹ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ These authors contributed equally.
⁴ 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.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.

Abstract

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.

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Abstract

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