Crnkl1 is a highly selective regulator of intron-retaining HIV-1 and cellular mrnas

Xiao H, Wyler E, Milek M, Grewe B, Kirchner P, Ekici AB, Silva ABOV, Jungnickl D, Full F, Thomas M, Landthaler M, Enßer A, Überla K (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 12

Pages Range: 1-24

Article Number: e02525-20

Journal Issue: 1

DOI: 10.1128/mBio.02525-20

Abstract

The HIV-1 Rev protein is a nuclear export factor for unspliced and incom-pletely spliced HIV-1 RNAs. Without Rev, these intron-retaining RNAs are trapped in the nucleus. A genome-wide screen identified nine proteins of the spliceosome, which all enhanced expression from the HIV-1 unspliced RNA after CRISPR/Cas knockdown. Depletion of DHX38, WDR70, and four proteins of the Prp19-associated complex (ISY1, BUD31, XAB2, and CRNKL1) resulted in a more than 20-fold enhancement of unspliced HIV-1 RNA levels in the cytoplasm. Targeting of CRNKL1, DHX38, and BUD31 affected nuclear export efficiencies of the HIV-1 unspliced RNA to a much larger extent than splicing. Transcriptomic analyses further revealed that CRNKL1 also suppresses cyto-plasmic levels of a subset of cellular mRNAs, including some with selectively retained introns. Thus, CRNKL1-dependent nuclear retention is a novel cellular mechanism for the regulation of cytoplasmic levels of intron-retaining HIV-1 mRNAs, which HIV-1 may have harnessed to direct its complex splicing pattern. IMPORTANCE To regulate its complex splicing pattern, HIV-1 uses the adaptor protein Rev to shuttle unspliced or partially spliced mRNA from the nucleus to the cyto-plasm. In the absence of Rev, these RNAs are retained in the nucleus, but it is unclear why. Here we identify cellular proteins whose depletion enhances cytoplas-mic levels of the HIV-1 unspliced RNA. Depletion of one of them, CRNKL1, also increases cytoplasmic levels of a subset of intron-retaining cellular mRNA, suggesting that CRNKL1-dependent nuclear retention may be a basic cellular mechanism exploited by HIV-1.

Authors with CRIS profile

Involved external institutions

Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch Germany (DE) Ruhr-Universität Bochum (RUB) Germany (DE)

How to cite

APA:

Xiao, H., Wyler, E., Milek, M., Grewe, B., Kirchner, P., Ekici, A.B.,... Überla, K. (2021). Crnkl1 is a highly selective regulator of intron-retaining HIV-1 and cellular mrnas. mBio, 12(1), 1-24. https://doi.org/10.1128/mBio.02525-20

MLA:

Xiao, Han, et al. "Crnkl1 is a highly selective regulator of intron-retaining HIV-1 and cellular mrnas." mBio 12.1 (2021): 1-24.

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