Highlights d 11,394 proteins are quantified in autopsy samples from 7 organs in 19 COVID-19 patients d Elevated expression of cathepsin L1 is detected in the COVID-19 lung tissue d Dysregulation of angiogenesis, coagulation, and fibrosis is detected in multiple organs d Systemic metabolic dysregulation is detected in multiple organs
Chemical RNA modifications are central features of epitranscriptomics, highlighted by the discovery of modified ribonucleosides in mRNA and exemplified by the critical roles of RNA modifications in normal physiology and disease. Despite a resurgent interest in these modifications, the biochemistry of 3-methylcytidine (mC) formation in mammalian RNAs is still poorly understood. However, the recent discovery of as the second gene responsible for mC presence in RNA in fission yeast raises the possibility that multiple enzymes are involved in mC formation in mammals as well. Here, we report the discovery and characterization of three distinct mC-contributing enzymes in mice and humans. We found that methyltransferase-like (METTL) 2 and 6 contribute mC in specific tRNAs and that METTL8 only contributes mC to mRNA. MS analysis revealed that there is an ∼30-40% and ∼10-15% reduction, respectively, in and null-mutant cells, of mC in total tRNA, and primer extension analysis located METTL2-modified mC at position 32 of tRNA isoacceptors and tRNA We also noted that METTL6 interacts with seryl-tRNA synthetase in an RNA-dependent manner, suggesting a role for METTL6 in modifying serine tRNA isoacceptors. , however, modified only mRNA, as determined by biochemical and genetic analyses in null-mutant mice and two human mutant cell lines. Our findings provide the first evidence of the existence of mC modification in mRNA, and the discovery of METTL8 as an mRNA mC writer enzyme opens the door to future studies of other mC epitranscriptomic reader and eraser functions.
The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues.
Chemical modification of transcripts with 5′ caps occurs in all organisms. Here, we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of an organism's cap epitranscriptome. The method was piloted with 21 canonical caps—m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG—and 5 ‘metabolite’ caps—NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, we discovered new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and high proportions of caps lacking 2′-O-methylation (m7Gpppm6A in mammals, m7GpppA in dengue virus). While substantial Dimroth-induced loss of m1A and m1Am arose with specific RNA processing conditions, human lymphoblast cells showed no detectable m1A or m1Am in caps. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.
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