Protein translation: biological processes and therapeutic strategies for human diseases

Abstract

Protein translation is a tightly regulated cellular process that is essential for gene expression and protein synthesis. The deregulation of this process is increasingly recognized as a critical factor in the pathogenesis of various human diseases. In this review, we discuss how deregulated translation can lead to aberrant protein synthesis, altered cellular functions, and disease progression. We explore the key mechanisms contributing to the deregulation of protein translation, including functional alterations in translation factors, tRNA, mRNA, and ribosome function. Deregulated translation leads to abnormal protein expression, disrupted cellular signaling, and perturbed cellular functions- all of which contribute to disease pathogenesis. The development of ribosome profiling techniques along with mass spectrometry-based proteomics, mRNA sequencing and single-cell approaches have opened new avenues for detecting diseases related to translation errors. Importantly, we highlight recent advances in therapies targeting translation-related disorders and their potential applications in neurodegenerative diseases, cancer, infectious diseases, and cardiovascular diseases. Moreover, the growing interest lies in targeted therapies aimed at restoring precise control over translation in diseased cells is discussed. In conclusion, this comprehensive review underscores the critical role of protein translation in disease and its potential as a therapeutic target. Advancements in understanding the molecular mechanisms of protein translation deregulation, coupled with the development of targeted therapies, offer promising avenues for improving disease outcomes in various human diseases. Additionally, it will unlock doors to the possibility of precision medicine by offering personalized therapies and a deeper understanding of the molecular underpinnings of diseases in the future.

Fig. 1

Protein translation deregulation and its related human disease. Protein translation includes three processes of initiation, elongation and termination. With the participation of ribosome, mRNA, tRNA, and translation related factors, the protein translation process enrolls in orderly to synthesis the nascent peptides accurately, thus, maintaining the cell proliferation and differentiation accurately. When this process is deregulated, the abundance, stability or functions of translated peptides alter and the cell fates run into disease states. Protein translation deregulation leads to neurodegenerative diseases, cancer, infectious diseases, cardiovascular diseases and other diseases

Fig. 2

Timeline of discoveries and Nobel Prize in the fields of protein translation

Fig. 3

The mechanism of protein translation process and protein translation deregulation manners. a Process of protein translation. 1. Translation initiation: The canonical translation initiation starts with recognizing and binding with 5′-cap domain of the mRNA by eIF4E complex in a cap dependent manner. After binding with cap, the mRNA translation is activated and recruits the 43 S ribosomal subunit to the 5’ end of the mRNA. Upon the 43 S ribosomal subunit scanning and recognizing the AUG start codon in the mRNA, 60 S ribosomal subunit is recruited and forms an 80 S ribosome complex to contribute for peptides elongation. noncanonical translation initiation vary in the aspects of eIFs categories, the cap recognition manner and the other conditions. The currently known noncanonical translation initiation includes m⁶A translation initiation, eIF3d translation initiation, IRESs-mediated translation initiation and ribosome shunting. 2. Translation elongation: In this process, the ribosome moves along the mRNA in the 5’ to 3’ direction with the attending of eEFs, the aminoacyl-tRNA in the A site forms a peptide bond with the growing polypeptide chain attached to the tRNA in the P site. The uncharged tRNA shifts from the P site to the E site and the peptidyl-tRNA from the A site to the P site. Then the uncharged tRNA in the E site is released from the ribosome, making way for the next aminoacyl-tRNA to enter the A site and repeat the process. 3. Translation termination: when ribosome complex recognizes a stop codon, termination is triggered. This process is mediated by the release factors eRF1 and eRF3. eRF1 regulates the nascent polypeptide release from the P-site peptidyl-tRNA, whereas eRF3 enhances polypeptide release. b Protein translation deregulation mechanism in mRNA, tRNA, translation factors and ribosome. mRNA: alternative splicing, mutation or modification in 5’ or 3’ UTR of mRNA. tRNA: mutation or modification of tRNA, tRNA deregulation and abnormal splicing. Translational factors: mutation, modification, abnormal expression and other variations. Ribosome: mutation or abnormal expression of ribosome components, ribosome stalling and so on

Fig. 4

Human diseases associated with protein translation deregulation. a Neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis) associated with protein translation deregulation. b Cancers (including lung cancer, breast cancer, liver cancer, ovarian cancer, colon cancer, pancreatic cancer, oral cancer, stomach cancer, esophageal cancer, and prostate cancer) associated with protein translation deregulation. c Infectious diseases (SARS-CoV-2, HIV, RSV) associated with protein translation deregulation. d Cardiovascular diseases associated with protein translation deregulation (Hypertrophic cardiomyopathy)

Fig. 5

Techniques used to study protein translation deregulation. a Ribosome profiling, a technique used to study protein translation deregulation. b Mass spectrometry-based proteomics, including protein quantification, phosphorylation quantification, and methylation quantification, used to study protein translation deregulation. c mRNA sequencing, including gene expression, alternative splicing, and mutation detection, used to study protein translation deregulation. d Single-cell approaches, including single-cell proteomics, single-cell ribosome profiling, and single-cell transcriptomics, used to study protein translation deregulation