Protein interaction and functional data indicate MTHFD2 involvement in RNA processing and translation

Abstract

BackgroundThe folate-coupled metabolic enzyme MTHFD2 is overexpressed in many tumor types and required for cancer cell proliferation, and is therefore of interest as a potential cancer therapeutic target. However, recent evidence suggests that MTHFD2 has a non-enzymatic function which may underlie the dependence of cancer cells on this protein. Understanding this non-enzymatic function is important for optimal targeting of MTHFD2 in cancer.MethodsTo identify potential non-enzymatic functions of MTHFD2, we defined its interacting proteins using co-immunoprecipitation and mass spectrometry and integrated this information with large-scale co-expression analysis, protein dynamics, and gene expression response to MTHFD2 knockdown.ResultsWe found that MTHFD2 physically interacts with a set of nuclear proteins involved in RNA metabolism and translation, including components of the small ribosomal subunit and multiple members of the RNA-processing hnRNP family. Interacting proteins were also in general co-expressed with MTHFD2 in experiments that stimulate or repress proliferation, suggesting a close functional relationship. Also, unlike other folate one-carbon enzymes, the MTHFD2 protein has a short half-life and responds rapidly to serum. Finally, shRNA against MTHFD2 depletes several of its interactors and yields an overall transcriptional response similar to targeted inhibition of certain ribosomal subunits.ConclusionsTaken together, our findings suggest a novel function of MTHFD2 in RNA metabolism and translation.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0185-4) contains supplementary material, which is available to authorized users.

The Prognostic Significance of Immune-Related Metabolic Enzyme MTHFD2 in Head and Neck Squamous Cell Carcinoma

“…In addition to its known function in mitochondrial folate metabolism, Nina reported that MTHFD2 was able to enter the nucleus and co-localize with DNA replication sites [19], which further supports its important regulatory roles in tumorigenesis. Costas also demonstrated that MTHFD2 interacted with many nuclear proteins associated with RNA metabolism and translation [20]. Further studies are warranted to elucidate the molecular mechanisms for the tumor promoting role of MTHFD2 in HNSCC.…”

MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK‐3β/β‐catenin signalling

“… 12 , 13 In addition to its canonical role to facilitate one‐carbon metabolism for purine synthesis, recent studies characterize MTHFD2 with redox defence, epigenetic modification, RNA translation and DNA repair. 14 , 15 , 16 , 17 Knockdown of MTHFD2 in colorectal cancer hinders NADPH production and makes cancer cells more sensitive to oxidative stress. 14 In renal cell carcinoma, MTHFD2 promotes the mRNA methylation of HIF‐2α via metabolic reprogramming.…”

Up-regulated Expression of MTHFD2 Correlates with Favorable Prognosis in LGG Patients: A Bioinformatic Analysis

“…MTHFD2-associated mTOR signaling pathway might exert protective effects on neuronal development in LGG. There was related study which suggests the novel function of MTHFD2 in RNA metabolism and translation, identifying as a potential non-enzymatic functions [30]. It follows that MTHFD2 has the potential to play a significant role in LGG through various pathways.…”