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Kim, Junsoo; Youn, Daehwa; Choi, Seunghoon; Lee, Youn Woo; Sumberzul, Dulguun; Yoon, Jeongeun; Lee, Hanju; Bae, Jong Woo; Noh, Hyuna; On, Dain; Hong, Seung-Min; An, Se-Hee; Jang, Hui Jeong; Kim, Seo Yeon; Kim, Young Been; Hwang, Ji-Yeon; Lee, Hyo-Jung; Bin Kim, Hong; Park, Jun Won; Yun, Jun-Won; Shin, Jeon-Soo; Seo, Jun-Young; Nam, Ki Taek; Choi, Kang-Seuk; Lee, Ho-Young; Chang, Hyeshik; Seong, Je Kyung; Cho, Jun
Experimental & molecular medicine, 12/2023, Letnik: 55, Številka: 12Journal Article
Translational regulation in tissue environments during in vivo viral pathogenesis has rarely been studied due to the lack of translatomes from virus-infected tissues, although a series of translatome studies using in vitro cultured cells with viral infection have been reported. In this study, we exploited tissue-optimized ribosome profiling (Ribo-seq) and severe-COVID-19 model mice to establish the first temporal translation profiles of virus and host genes in the lungs during SARS-CoV-2 pathogenesis. Our datasets revealed not only previously unknown targets of translation regulation in infected tissues but also hitherto unreported molecular signatures that contribute to tissue pathology after SARS-CoV-2 infection. Specifically, we observed gradual increases in pseudoribosomal ribonucleoprotein (RNP) interactions that partially overlapped the trails of ribosomes, being likely involved in impeding translation elongation. Contemporaneously developed ribosome heterogeneity with predominantly dysregulated 5 S rRNP association supported the malfunction of elongating ribosomes. Analyses of canonical Ribo-seq reads (ribosome footprints) highlighted two obstructive characteristics to host gene expression: ribosome stalling on codons within transmembrane domain-coding regions and compromised translation of immunity- and metabolism-related genes with upregulated transcription. Our findings collectively demonstrate that the abrogation of translation integrity may be one of the most critical factors contributing to pathogenesis after SARS-CoV-2 infection of tissues.
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in: SICRIS
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