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larp6

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Official Full Name
La ribonucleoprotein domain family, member 6
Synonyms
LARP6; La ribonucleoprotein domain family, member 6; la-related protein 6; acheron; FLJ11196; Achn; La ribonucleoprotein domain family member 6; LARP6_HUMAN; death-associated LA motif protein; fi75f12; zgc:66107; wu:fi75f12; ZFOS-508H5.1

Recent Progress

The La ribonucleo protein domain family member 6 (LARP6), is an important protein in many ways. It is mainly localized to the microtubules and the cytokinetic bridge (Fig.1). To begin with, there are about 800 RNA binding proteins, but only one, LARP6, is specifically involved in type I collagen upregulation, which occurs in reparative or reactive fibrosis. Posttranscriptional regulation evidently plays a predominant role. In the 5′untranslated region (5’UTR) of mRNAs encoding for type I and type III collagens, there is an evolutionally conserved stem-loop (SL) structure. LARP6 binds to the 5′SL in sequence specific manner to regulate stability of collagen mRNAs and their translatability. More specifically, it has been proposed that collagen mRNAs are targeted to the membrane of the endoplasmic reticulum (ER) after translation of the signal peptide and by signal peptide recognition particle (SRP). It was shown by the researchers that knock down of LARP6 releases a small amount of collagen mRNAs from the membrane. Depolimerization of nonmuscle myosin filaments has a similar, but stronger effect. In the absence of LARP6 or nonmuscle myosin, filaments collagen polypeptides become hypermodified and are poorly secreted in the cytosol. This indicates hypermodifications and misfolding may lead to lack of coordination of their synthesis and retro-translocation. Moreover, it was postulated that collagen mRNAs directly partition to the ER membrane prior to synthesis of the signal peptide and that LARP6 along with nonmuscle myosin filaments mediate this process. In further elucidating the posttranslational modifications of LARP6 and how they affect type I collagen, researchers showed that in lung fibroblasts LARP6 is phosphorylated at 8 serines, 6 of which are located within C-terminal domain. Moreover, phosphorylation of LARP6 follows a hierarchical order. Inhibition of PI3K/Akt pathway reduced the phosphorylation of LARP6, but had no effect on the S451A mutant, suggesting that PI3K/Akt pathway targets S451 and Akt has been identified as the responsible kinase. It was concluded that LARP6 phosphorylation at S451 is critical for regulating translation and folding of collagen polypeptides.

LARP6 Fig. 1. LARP6 in human cells. (MC Ryan et al, 2016)

Given the relationship between Larp6 and type I collagen, researchers hypothesized that DPP4 gene (dipeptidyl peptidase 4, inhibition of which has been shown to improve proteinuria in humans with Type 2 diabetes) deletion will prevent Larp6-mediated fibrosis in progressive kidney disease. In the study, an increase in kidney Larp6 protein was observed in both the obese and the renin-angiotensin-aldosterone system (RAAS) activation models. Furthermore, Larp6 protein levels were significantly lowered in the DPP4 knockout mice. These findings suggested that in conditions of progressive kidney injury, both DPP4 and Larp6 are activated. Moreover, DPP4 may regulate Larp6 expression and kidney fibrosis, thereby identifying DPP4 inhibition as a viable strategy to mitigate progressive kidney injury that may lead to end stage kidney disease and dialysis.

The connection between IGF-1 (insulin-like growth factor-1) and LARP6 has also been determined. It has been found that in human aortic smooth muscle cells (SMCs), IGF-1 rapidly increased LARP6 expression and the rate of collagen synthesis and extracellular accumulation. IGF-1 increased both LARP6 and collagen type I expression. IGF-1 increased the level of COL1a1 and COL1a2 mRNA bound to LARP6. Mutation of the 5' stem-loop of Col1a1 mRNA, which inhibits binding of LARP6, abolished the ability of IGF-1 to increase synthesis of collagen type I. Furthermore, overexpression of a 5' stem-loop RNA molecular decoy that sequesters LARP6, prevented the ability of IGF-1 to increase pro-α1(I) and mature α1(I) expression in cultured medium. In conclusion, it was identified that LARP6 as a critical mediator by which IGF-1 augments synthesis of collagen type I in vascular smooth muscle, which may play an important role in promoting atherosclerotic plaque stability.

References:

  1. Zhang, Yujie, and B. Stefanovic. "LARP6 Meets Collagen mRNA: Specific Regulation of Type I Collagen Expression." International Journal of Molecular Sciences 17.3(2016):419.
  2. Wang, H., and B. Stefanovic. "Role of LARP6 and Nonmuscle Myosin in Partitioning of Collagen mRNAs to the ER Membrane." Plos One 9.10(2014):e108870.
  3. Zhang, Yujie, and S. Branko. "Akt mediated phosphorylation of LARP6; critical step in biosynthesis of type I collagen:." Scientific Reports 6(2016):22597.
  4. Stefanovic, L, et al. "Characterization of binding of LARP6 to the 5' stem-loop of collagen mRNAs: Implications for synthesis of type I collagen." Rna Biology 11.11(2014):1386-1401.
  5. Martino, L., et al. "1H, 15N and 13C chemical shift assignments of the La motif and RRM1 from human LARP6." Biomolecular Nmr Assignments 9.2(2015):1-4.
  6. Martino, L, et al. "Synergic interplay of the La motif, RRM1 and the interdomain linker of LARP6 in the recognition of collagen mRNA expands the RNA binding repertoire of the La module." Nucleic Acids Research 43.1(2015):645.
  7. Blackstock, et al. "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." Journal of Biological Chemistry 289.11(2014):7264-7274.