The role of LARP1 in translation and beyond

Abstract

The LARP1 proteins form an evolutionarily homogeneous subgroup of the eukaryotic superfamily of La-Motif (LAM) containing factors. Members of the LARP1 family are found in most protists, fungi, plants, and animals. We review here evidence suggesting that LARP1 are key versatile messenger RNA (mRNA)-binding proteins involved in regulating important biological processes such as gametogenesis, embryogenesis, sex determination, and cell division in animals, as well as acclimation to stress in yeasts and plants. LARP1 proteins perform all these essential tasks likely by binding to key mRNAs and regulating their stability and/or translation. In human, the impact of LARP1 over cell division and proliferation is potentially under the control of the TORC1 complex. We review data suggesting that LARP1 is a direct target of this master signaling hub. TOR-dependent LARP1 phosphorylation could specifically enhance the translation of TOP mRNAs providing a way to promote translation, growth, and proliferation. Consequently, LARP1 is found to be significantly upregulated in many malignant cell types. In plants, LARP1 was found to act as a cofactor of the heat-induced mRNA degradation process, an essential acclimation strategy leading to the degradation of more than 4500 mRNAs coding for growth and development housekeeping functions. In Saccharomyces cerevisiae, the LARP1 proteins (Slf1p and Sro9p) are important, among other things, for copper resistance and oxidative stress survival. LARP1 proteins are therefore emerging as critical ancient mRNA-binding factors that evolved common as well as specific targets and regulatory functions in all eukaryotic lineages.

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

“…LARP1 has been previously shown to be an mTORC1 effector and has been implicated as an important regulator of mRNA translation. [43][44][45][46] It is important to note that the serine 526 site found altered in our phosphoproteomics results is a different phosphorylation site than those previously proposed to be regulated by mTORC1. [47][48][49] We demonstrated an interaction between CDK9 and LARP1 through co-IP ( Figure 5B-C).…”

Auxin Signaling in Regulation of Plant Translation Reinitiation

“…However, the underlying molecular mechanisms that affect protein synthesis efficiency are largely unknown and in need of further research. A recent study revealed that heat stress can rapidly induce an mRNA degradation process where involving LARPs (La and related Proteins) (Deragon and Bousquet-Antonelli, 2015). Strikingly, mammalian LARP1 was implicated in translation regulation of TOP (5′-terminal oligopyrimidine tract)-containing mRNAs under the control of TOR (Tcherkezian et al, 2014); however, whether translation of many plant TOP-containing mRNAs (Dobrenel et al, 2016) depends on TOR remains to be identified.…”

Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer

“…In this regard, while the anti-cancer cell and anti-cell proliferation effects of mTORC1 inhibition involve the downregulation of protein synthesis, possibly selectively, mTORC1 also impacts on other key pathways and proteins that regulate cell proliferation and survival. These include mTOR regulation by phosphorylation of the autophagy pathway (36) through the ULK1-mAtg13-FIP200 complex (37), the growth factor receptor bound protein 10 (Grb10) protein which blocks growth factor mitogenic signaling (38, 39), and the phosphorylation of mRNA binding proteins such as LARP1 that regulates cell division (40), among others. Consequently, if chemotherapy resistance can be reversed through mTOR inhibition, it might or might not directly involve mTORC1 phosphorylation of protein synthesis effectors S6K and 4E-BP1.…”