Translational regulation through ribosome-associated quality control and ribotoxic stress in human diseases

Abstract

Ribosome-associated quality control (RQC) and ribotoxic stress response (RSR) are critical cellular mechanisms for maintaining protein homeostasis under stress and safeguarding against translational disruptions and pathological processes. The RQC pathway is a co-translational surveillance system activated by ribosomal collisions, which may arise from defective mRNAs, stalled ribosomes, or stress- inducing agents like UV radiation and ribotoxins. The RQC pathway is essential for the recognition and degradation of faulty or incomplete translational products. In detail, it is initiated by the ubiquitin ligase ZNF598, which manages stalled ribosomes by tagging their small subunit proteins for ubiquitination, recruiting additional RQC factors such as NEMF and LTN1, and clearing aberrant polypeptides to maintain proteostasis. These pathways are closely intertwined with other stress responses, including the integrated stress response (ISR) and RSR, which activate upon ribosomal collision to determine cell fate adaptively under various stress conditions. Among the various cellular stress conditions, ribotoxic stress is triggered by damage to ribosomes or interference with their function during translation. This stress often results from exposure to ribotoxic agents such as UV radiation, oxidative stress, translation inhibitors, chemotherapeutic agents, or bacterial toxins that impair the ribosome’s catalytic activity and lead to the activation of the RSR. The RSR is a signaling pathway induced by ribosomal collision and occurs for several reasons that mRNA damage, defecting translation process, and slowdown of translation. RSR is induced by ZAKα (Sterile alpha motif and leucine zipper kinase), also known as MAP3K20 as inducing cell cycle arrest or apoptosis through p38 or JNK signaling pathway. These mechanisms are especially significant in the context of human diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as well as in certain human cancers. In ALS/FTD linked to C9ORF72 mutations, the presence of toxic dipeptide repeat (DPR) proteins such as poly(GR) expansions disrupt normal translation and induces ribosomal stalling. ZNF598 has been identified as a crucial modulator of RQC activity in these neurodegenerative diseases. It co-translationally regulates the accumulation of poly(GR) by promoting its degradation through the ubiquitin-proteasome pathway, limiting its cytotoxic effects. Studies in human and Drosophila models reveal that ZNF598 overexpression reduces nuclear poly(GR) accumulation and neurotoxicity, while ZNF598 deletion exacerbates it. A key observation in C9-ALS patient-derived neurons is that ALS- related mutations in ZNF598 impair RQC function, leading to an accumulation of toxic poly(GR) proteins, elevated caspase-3 activation, and neuronal apoptosis. The ability of RQC pathways, particularly through ZNF598, to mitigate neurotoxicity suggests a protective role for RQC in ALS/FTD pathogenesis, positioning RQC enhancement as a potential therapeutic strategy for neurodegenerative diseases. Chronic myeloid leukemia (CML) is a type of cancer that is derived from certain blood- forming cells of the bone marrow. In CML, a genetic change occurs in the myeloid cells in the bone marrow. This genetic change leads to the formation of an abnormal gene called BCR-ABL. This fusion gene produces tyrosine kinase, which promotes excessive production of white blood cells. For CML therapy, tyrosine kinase inhibitors (TKIs) specifically target the BCR-ABL. In CML cells with the pathogenic BCR-ABL fusion protein, ribosome collisions increase significantly when treated with TKIs, leading to activation of RSR through the MAP3 kinase ZAK. This pathway initiates phosphorylation cascades that drive cellular apoptosis under conditions of translational stress. ZAK expression levels in CML are notably high during the aggressive blast crisis phase, suggesting a strong association between ZAK-mediated RSR and disease progression. Depletion of ZAK in CML cells demonstrates a significant reduction in TKIs-induced apoptosis, highlighting the role of ZAK in facilitating cell death under ribotoxic stress. Additionally, pharmacological agents that induce ribosomal collisions, such as anisomycin (ANS), emetine (EME) and homoharringtonine (HHT), have been shown to synergize with TKIs to enhance anti-leukemic effects, specifically targeting the ribotoxic vulnerabilities of CML cells. In summary, these findings underscore the therapeutic potential of modulating ribosome- associated quality control and ribotoxic stress pathways across different diseases. In neurodegenerative diseases like ALS/FTD, enhancing RQC through upregulation of ZNF598 or other RQC factors may reduce the accumulation of neurotoxic proteins, offering a neuroprotective approach. Meanwhile, in cancers such as CML, targeting RSR components like ZAK can exploit ribotoxic vulnerabilities, selectively promoting apoptosis in malignant cells without affecting normal cells. Exploring the molecular mechanism of RQC and RSR sheds light on their roles in disease pathogenesis and highlights potential therapeutic avenues.