A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs

Abstract

Type I collagen is composed of two a1(I) polypeptides and one a2(I) polypeptide and is the most abundant protein in the human body. Expression of type I collagen is primarily controlled at the level of mRNA stability and translation. Coordinated translation of a(I) and a2(I) mRNAs is necessary for efficient folding of the corresponding peptides into the collagen heterotrimer. In the 59 untranslated region (59 UTR), collagen mRNAs have a unique 59 stem-loop structure (59 SL). La ribonucleoprotein domain family member 6 (LARP6) is the protein that binds 59 SL with high affinity and specificity and coordinates their translation. Here we show that RNA helicase A (RHA) is tethered to the 59 SL of collagen mRNAs by interaction with the C-terminal domain of LARP6. In vivo, collagen mRNAs immunoprecipitate with RHA in an LARP6-dependent manner. Knockdown of RHA prevents formation of polysomes on collagen mRNAs and dramatically reduces synthesis of collagen protein, without affecting the level of the mRNAs. A reporter mRNA with collagen 59 SL is translated three times more efficiently in the presence of RHA than the same reporter without the 59 SL, indicating that the 59 SL is the cis-acting element conferring the regulation. During activation of quiescent cells into collagen-producing cells, expression of RHA is highly up-regulated. We postulate that RHA is recruited to the 59 UTR of collagen mRNAs by LARP6 to facilitate their translation. Thus, RHA has been discovered as a critical factor for synthesis of the most abundant protein in the human body.

In Vitro and In Vivo Analysis of the Interaction between RNA Helicase A and HIV-1 RNA

“…Lin28 recognizes specific sequences in a subset of mRNAs, and its direct interaction with RHA is believed to result in the recruitment of RHA to the translational machinery, resulting in the stimulation of translation (26). A similar phenomenon was observed for LARP6, a member of the La ribonucleoprotein domain family, where LARP6 was shown to bind to both specific sequences in the 5=-UTR of collagen mRNA and to RHA, thereby directing RHA to this site (34). Directed RHA binding may also occur when RHA binds to the transcription factors CREB binding protein (CBP) and RNA polymerase II (2).…”

“…The stimulatory effect of RHA on translation might involve direct binding to the highly structured 5=-untranslated region (5=-UTR) in retrovirus mRNA, with a possible unwinding of this region to facilitate ribosomal scanning (22). However, for other target cellular mRNAs, RHA's stimulatory effect on translation appears to result from RHA's recruitment to the translational machinery via its interaction with other mRNA binding proteins such as Lin28 (26) or an La ribonucleoprotein domain family member, LARP6 (34). These examples make it clear that the roles of RHA in regulating multiple stages of RNA metabolism are likely to be regulated by its interaction with specific proteins and/or RNA structures.…”

Insulin-like Growth Factor-1 Increases Synthesis of Collagen Type I via Induction of the mRNA-binding Protein LARP6 Expression and Binding to the 5′ Stem-loop of COL1a1 and COL1a2 mRNA

“…Asterisks (*) indicate statistically significant difference from control (serum-free medium, 0 ng/ml IGF-1); n ϭ 8 -12, Mean Ϯ S.E., *, p Ͻ 0.05; **, p Ͻ 0.01; ***, p Ͻ 0.001. mRNA-binding protein, LARP6, could play a role in the ability of IGF-1 to increase collagen type I. LARP6 binds to the 5Ј stem-loop secondary structure present in COL1a1 and COL1a2 mRNAs, and regulates efficient translation of the collagen type I heterotrimer (5,(11)(12)(13). IGF-1 induced a significant increase in expression of LARP6 within 3 h (2.9-fold, p Ͻ 0.01), and this increase was sustained at 24 h (p Ͻ 0.01, Fig.…”

LARP4B is an AU-rich sequence associated factor that promotes mRNA accumulation and translation

“…LARP6 has been shown to interact with a hairpin structure located in the 5 ′ untranslated region (UTR) of the mRNA encoding collagen. Binding resulted in the stimulation of collagen mRNA translation, thus identifying LARP6 as a positive translation factor (Cai et al 2010a,b;Challa and Stefanovic 2011;Manojlovic and Stefanovic 2012;Wang and Stefanovic 2014). Whereas LARP6 likely targets only a small number of mRNAs carrying a specific secondary sequence motif in cis, LARP1 and LARP4 appear to influence translation in a broader sense.…”