Abstract
The cellular function of the cancer-associated RNA-binding protein La has been linked to translation of viral and cellular mRNAs. Recently, we have shown that the human La protein stimulates IRES-mediated translation of the cooperative oncogene CCND1 in cervical cancer cells. However, there is little known about the underlying molecular mechanism by which La stimulates CCND1 IRES-mediated translation, and we propose that its RNA chaperone activity is required. Herein, we show that La binds close to the CCND1 start codon and demonstrate that La's RNA chaperone activity can change the folding of its binding site. We map the RNA chaperone domain (RCD) within the C-terminal region of La in close proximity to a novel AKT phosphorylation site (T389). Phosphorylation at T389 by AKT-1 strongly impairs its RNA chaperone activity. Furthermore, we demonstrate that the RCD as well as T389 is required to stimulate CCND1 IRES-mediated translation in cells. In summary, we provide a model whereby a novel interplay between RNA-binding, RNA chaperoning and AKT phosphorylation of La protein regulates CCND1 IRES-mediated translation.
Highlights
The La protein (LARP3) is a cancer-associated RNAbinding protein [1,2,3,4,5,6] initially identified as autoantigen in patients suffering from lupus erythematosus and Sjogren’s syndrome [7,8]
We have shown recently that the human La protein interacts with endogenous cyclin D1 (CCND1) mRNA and stimulates CCND1 internal ribosome entry site (IRES) (D1-IRES)-mediated mRNA translation [3]
We further demonstrate that the RNA chaperone activity of La is required to facilitate CCND1 IRES-mediated mRNA translation in cells and can be regulated by a nearby AKT-1 phosphorylation site (T389)
Summary
The La protein (LARP3) is a cancer-associated RNAbinding protein [1,2,3,4,5,6] initially identified as autoantigen in patients suffering from lupus erythematosus and Sjogren’s syndrome [7,8]. The La protein is implicated in many steps of the cellular and viral RNA metabolism including processing of RNA polymerase III transcripts, micro RNA processing and mRNA stabilization [9,10,11,12,13,14,15,16,17,18,19]. The multifunctional RNA-binding protein shuttles between the nucleus and the cytoplasm [2,20,21,22]. Several reports suggest that La is involved in translational regulation of viral and cellular RNAs with structure 5 untranslated regions (5 -UTRs). Some of those mRNAs contain an internal ribosome entry site (IRES) in their 5 -UTR allowing translational initiation when cap-dependent translation is impaired [33,34,35]. The molecular mechanism by which La supports mRNA translation is still inexplicable
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