Key result
Genetic depletion of DDX3 in Leishmania slows ribosome movement, impairs translation elongation, and decreases de novo protein synthesis, triggering co-translational quality control.
DDX3 plays a crucial role in optimal translation elongation by preventing prolonged stalls and stimulating recycling of arrested ribosomes in Leishmania.
DDX3 is a multifaceted RNA helicase of the DEAD-box family that plays central roles in all aspects of RNA metabolism including translation initiation. Here, we provide evidence that the Leishmania DDX3 ortholog functions in post-initiation steps of translation. We show that genetic depletion of DDX3 slows down ribosome movement resulting in elongation-stalled ribosomes, impaired translation elongation and decreased de novo protein synthesis. We also demonstrate that the essential ribosome recycling factor Rli1/ABCE1 and termination factors eRF3 and GTPBP1 are less recruited to ribosomes upon DDX3 loss, suggesting that arrested ribosomes may be inefficiently dissociated and recycled. Furthermore, we show that prolonged ribosome stalling triggers co-translational ubiquitination of nascent polypeptide chains and a higher recruitment of E3 ubiquitin ligases and proteasome components to ribosomes of DDX3 knockout cells, which further supports that ribosomes are not elongating optimally. Impaired elongation of translating ribosomes also results in the accumulation of cytoplasmic protein aggregates, which implies that defects in translation overwhelm the normal quality controls. The partial recovery of translation by overexpressing Hsp70 supports this possibility. Collectively, these results suggest an important novel contribution of DDX3 to optimal elongation of translating ribosomes by preventing prolonged translation stalls and stimulating recycling of arrested ribosomes.
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Padmanabhan et al. (2021) studied this question. Genetic depletion of DDX3 vs. Control cells was evaluated on Ribosome movement, translation elongation, and de novo protein synthesis. Genetic depletion of DDX3 in Leishmania slows ribosome movement, impairs translation elongation, and decreases de novo protein synthesis, triggering co-translational quality control.
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