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

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. One-Sentence Summary LARP1 directly binds free ribosomal subunits to repress TOP mRNAs ### Competing Interest Statement 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.