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A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13

View ORCID ProfileElena Vialetto, View ORCID ProfileYanying Yu, Scott P. Collins, View ORCID ProfileKatharina G. Wandera, View ORCID ProfileLars Barquist, Chase L. Beisel
doi: https://doi.org/10.1101/2021.11.23.469693
Elena Vialetto
1Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI), 97080 Würzburg, Germany
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  • ORCID record for Elena Vialetto
Yanying Yu
1Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI), 97080 Würzburg, Germany
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Scott P. Collins
2Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA
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Katharina G. Wandera
1Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI), 97080 Würzburg, Germany
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Lars Barquist
1Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI), 97080 Würzburg, Germany
3Medical Faculty, University of Würzburg, 97080 Würzburg, Germany
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Chase L. Beisel
1Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI), 97080 Würzburg, Germany
2Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA
3Medical Faculty, University of Würzburg, 97080 Würzburg, Germany
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  • For correspondence: chase.beisel@helmholtz-hiri.de
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SUMMARY

Immune systems must recognize and clear foreign invaders without eliciting autoimmunity. CRISPR-Cas immune systems in prokaryotes manage this task by following two criteria: extensive guide:target complementarity and a defined target-flanking motif. Here we report an additional requirement for RNA-targeting CRISPR-Cas13 systems: expression of the target transcript exceeding a threshold. This finding is based on targeting endogenous non-essential transcripts, which rarely elicited dormancy through collateral RNA degradation. Instead, eliciting dormancy required over-expressing targeted transcripts above a threshold. A genome-wide screen confirmed target expression levels as the principal determinant of cytotoxic autoimmunity and revealed that the threshold shifts with the guide:target pair. This expression threshold ensured defense against a lytic bacteriophage yet allowed tolerance of a targeted beneficial gene expressed from an invading plasmid. These findings establish target expression levels as a third criterion for immune activation by RNA-targeting CRISPR-Cas systems, buffering against autoimmunity and distinguishing pathogenic and benign invaders.

HIGHLIGHTS

  • Cas13-induced dormancy requires RNA target levels to exceed an expression threshold

  • The expression threshold can prevent cytotoxic self-targeting for endogenous transcripts

  • The threshold shifts depending on the CRISPR RNA guide:target pair

  • The threshold allows cells to distinguish pathogenic and benign infections

Competing Interest Statement

C.L.B. is a co-founder and member of the Scientific Advisory Board for Locus Biosciences as well as a member of the Scientific Advisory Board for Benson Hill. The other authors have no conflicts of interest to declare.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 23, 2021.
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A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13
Elena Vialetto, Yanying Yu, Scott P. Collins, Katharina G. Wandera, Lars Barquist, Chase L. Beisel
bioRxiv 2021.11.23.469693; doi: https://doi.org/10.1101/2021.11.23.469693
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A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13
Elena Vialetto, Yanying Yu, Scott P. Collins, Katharina G. Wandera, Lars Barquist, Chase L. Beisel
bioRxiv 2021.11.23.469693; doi: https://doi.org/10.1101/2021.11.23.469693

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