Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection

Abstract

Translational control at the initiation, elongation, and termination steps exerts immediate effects on the rate as well as the spatiotemporal dynamics of new protein synthesis, shaping the composition of the proteome. Translational control is particularly important for cells under stress as during viral infection or in disease conditions such as cancer and neurodegenerative diseases. Much has been learned about the control mechanisms acting at the translational initiation step under normal or pathological conditions. However, problems during the elongation or termination steps of translation can lead to ribosome stalling and ribosome collision, which will trigger ribosome-associated quality control (RQC) mechanism. Inadequate RQC may lead to the accumulation of faulty translation products that perturb protein homeostasis (proteostasis). Proteostasis signifies a cellular state in which the synthesis, folding, and degradation of proteins are maintained at a homeostatic state such that an intact proteome is preserved. Cellular capacity to preserve proteostasis declines with age, which is thought to contribute to age-related diseases. Proteostasis failure manifested as formation of aberrant protein aggregates, epitomized by the amyloid plaques in Alzheimer’s disease (AD), is a defining feature of neurodegenerative diseases. The root cause of the proteostasis failure and protein aggregation is still enigmatic. Here I will review recent studies supporting that faulty translation products resulting from inadequate RQC of translational stalling and ribosome collision during the translation of problematic mRNAs can be the root cause of proteostasis failure and may represent novel therapeutic targets for neurodegenerative diseases. I will also review evidence that translation regulation by RQC is operative in cancer cells and during viral infection. Better understanding of RQC mechanism may lead to novel therapeutic strategies against neurodegenerative diseases, cancer, and viral infections, including the ongoing COVID-19 pandemic.

Reverse electron transfer is activated during aging and contributes to aging and age‐related disease

“…How mitochondrial RET is mechanistically linked to the RQC of translational stalling and ribosome collision during APP/APP.C99 protein synthesis, which occurs at the ER translocon (Rimal et al, 2021), is an intriguing question that warrants further investigation. Nevertheless, our findings of a tight correlation between the beneficial effect of RET manipulations in the AD model, either genetically or pharmacologically, and the removal of proteostasis-perturbing aberrant APP.C99 species resulting from inadequate RQC of translation stalling and ribosome collision, offer further support for the hypothesis that translation stalling and ribosome collision is central to AD pathogenesis (Lu, 2022).…”

SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

“…TTP and its paralogues ZFP36L1 and ZFP36L2 have significant roles in cancer[55] and regulation of the immune system[55] through binding and repressing the expression of mRNAs that contain the A/U rich element. A recent study also revealed the biological importance of RQC in neurological disorders [56]. Future studies will assess the impact of NSP2 on other functions of the GIGYF2/4EHP complex, such as TTP and RQC, and the biological pathways they control.…”

Translation of zinc finger domains induces ribosome collision and Znf598-dependent mRNA decay in vertebrates

“…The ribosome lies at the core of such translational quality control mechanisms; aberrant positioning, movement, and structure of ribosomes during mRNA translation serve as cues to trigger specific quality control pathways [2,3]. The failure of translational quality control pathways results in the production of harmful proteins and protein aggregates, leading to pathogenic outcomes [4][5][6].…”

“…The massive decay of maternal mRNA and concurrent zygotic genome activation (ZGA) constitute a conserved developmental transition in metazoans called the maternal-to-zygotic transition (MZT) [44][45][46][47]. The molecular mechanisms underlying MZT have been extensively characterized in zebrafish, in which codon-mediated decay and zygotically transcribed miR-430 play pivotal roles in maternal mRNA clearance in combination with m 6 A modification [48][49][50][51][52][53]. By combining a zebrafish mutant of znf598 and a reporter mRNA containing a ribosome stall sequence, we previously showed that ribosome stalling induces mRNA decay in a Znf598-dependent manner, demonstrating that NGD is active during the MZT [37].…”