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. 2022 Mar 2;50(5):2782–2806. doi: 10.1093/nar/gkac132

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© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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Figure 9. — Model how hnRNP D regulates HPV16 E6/E7 mRNA splicing. (A) In regular condition, four splice isoforms of HPV16 E6/E7 mRNAs are produced. This is regulated by fine-tuned recruitment of cellular U1 spliceosome factor to HPV16 E6/E7 splice donor SD226 and that of U2 spliceosome factors to HPV16 E6/E7 splice acceptors SA409, SA526 or SA742. (B) hnRNP D40 binds to both U1 spliceosome factor and U2 spliceosome factor at its C-terminus and with some extent at its N-terminus, which inhibits spliceosome factor activity. This inhibitory function is mediated by N-terminus of hnRNP D. At the same time, hnRNP D interacts with several sites in HPV16 E6/E7 coding RNAs at its RRM1/RRM2 domain. As a result, hnRNP D mainly inhibits 226∧409 splicing on the HPV16 E6/E7 mRNAs. The intron-retained E6 mRNAs are accompanied by hnRNP D to the cytoplasm. However, hnRNP D association on intron-retained E6 mRNA suppresses translation of E6 protein by unknown mechanism. To enhance translation of HPV16 E6 protein from intron-retained E6 mRNA, hnRNP D40 must need to be replaced from intron-retained E6 mRNA. (C) Deletion mutant of hnRNP D40, D1 that doesn’t possess N-terminal A-rich and exon 2 but harbors intact RRM1/RRM2 domain and C-terminus, still has potential to interact with spliceosome factors and with HPV16 RNA though it loses inhibitory effect on spliceosome factors. As a result, D1 mutant mediates recruitment of spliceosome factors to HPV16 splice sites, thereby increasing HPV16 E6/E7 mRNA splicing.