RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function

Abstract

Although several ribosomal protein paralogs are expressed in a tissue-specific manner, how these proteins affect translation and why they are required only in certain tissues have remained unclear. Here we show that RPL3L, a paralog of RPL3 specifically expressed in heart and skeletal muscle, influences translation elongation dynamics. Deficiency of RPL3L-containing ribosomes in RPL3L knockout male mice resulted in impaired cardiac contractility. Ribosome occupancy at mRNA codons was found to be altered in the RPL3L-deficient heart, and the changes were negatively correlated with those observed in myoblasts overexpressing RPL3L. RPL3L-containing ribosomes were less prone to collisions compared with RPL3-containing canonical ribosomes. Although the loss of RPL3L-containing ribosomes altered translation elongation dynamics for the entire transcriptome, its effects were most pronounced for transcripts related to cardiac muscle contraction and dilated cardiomyopathy, with the abundance of the encoded proteins being correspondingly decreased. Our results provide further insight into the mechanisms and physiological relevance of tissue-specific translational regulation.

An “alert state” ribosome population acts as a master regulator of cytokine-mediated processes

“…The fact that the ribosome itself is at the center of this regulation is in fitting with recent reports of direct regulation of phenotypes by the ribosome 22,53–55 . Indeed, it has previously been hypothesized that an “immunoribosome” exists 28 , which was defined as a subset of ribosomes dedicated to translating DRiPs for HLA I immunosurveillance 13,14 , thus altering the antigen repertoire.…”

Proteomics-based characterization of ribosome heterogeneity in adult mouse organs

“…Several studies describe that such a “paralogous RP signature” ensures specific functions through selective translation, e.g. muscle function (32,64) or gonad specification and function (55,65). In yeast, the balance between two RP forms controls proper mitochondrial function (66) and response to stress (67).…”

Cardiomyocyte-Specific Loss of Glutamyl-prolyl-tRNA Synthetase Leads to Disturbed Protein Homeostasis and Dilated Cardiomyopathy

“…However, we observed the significant upregulation of ribosome protein RPL3 and the downregulation of RPL3L, indicating that the ratio of RPL3/RPL3L is drastically increased ( Figure S4A ). It is known that RPL3L is CM-specific and cardioprotective, while RPL3 possibly plays a detrimental role [ 37 , 38 ]. These integrated multi-omics data reveal multiple aspects of disrupted protein homeostasis upon genetic inactivation of Eprs1 , including (1) a global increase in ribosome protein-coding mRNAs through increased Myc expression and mTORC1 activity [ 39 ]; (2) the inhibition of cap-dependent translation initiation by ISR activation [ 40 ]; (3) a decrease in CM-specific ribosome protein RPL3L and an increase in its homolog protein RPL3 may change ribosome heterogeneity [ 37 , 38 ] (more RPL3-bearing ribosome than RPL3L-bearing ribosome in the cKO hearts).…”

“…It is known that RPL3L is CM-specific and cardioprotective, while RPL3 possibly plays a detrimental role [ 37 , 38 ]. These integrated multi-omics data reveal multiple aspects of disrupted protein homeostasis upon genetic inactivation of Eprs1 , including (1) a global increase in ribosome protein-coding mRNAs through increased Myc expression and mTORC1 activity [ 39 ]; (2) the inhibition of cap-dependent translation initiation by ISR activation [ 40 ]; (3) a decrease in CM-specific ribosome protein RPL3L and an increase in its homolog protein RPL3 may change ribosome heterogeneity [ 37 , 38 ] (more RPL3-bearing ribosome than RPL3L-bearing ribosome in the cKO hearts). Together, these events perturb the proteomic homeostasis in Eprs1 cKO hearts, which may contribute to the progression of heart failure in mice ( Figure 2 ).…”