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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Escherichia coli str. K-12 substr. MG1655

PROVIDER: GSE179915 | GEO | 2022/06/08

REPOSITORIES: GEO

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

Project description:CRISPR-Cas systems must enact robust immunity against foreign genetic material without inducing cytotoxic autoimmunity. For type VI systems that use Cas13 nucleases and recognize RNA targets, immune activation requires extensive CRISPR RNA (crRNA) guide-target complementarity and a target-flanking motif. Here, we report a third requirement shaping the immune response: the expression of the target transcript exceeding a threshold. We found that endogenous non-essential transcripts targeted by crRNAs rarely elicited autoimmunity. Instead, autoimmune induction required over-expressing the targeted transcripts above a threshold. A genome-wide screen confirmed target expression levels as a global determinant of cytotoxic autoimmunity and revealed that this threshold shifts with each guide-target pair. This threshold further ensured defense against a lytic bacteriophage yet allowed the tolerance of a targeted beneficial gene expressed from an invading plasmid. These findings establish target expression levels as an additional criterion for immune defense by RNA-targeting CRISPR-Cas systems, preventing autoimmunity and distinguishing pathogenic and benign invaders.

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A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13 [RNA-seq]

Project description:The study investigates how varying target expression levels influences self-targeting and defense using Cas13a. We see how immunity is activated only over a target transcription threshold, which is variable between targets. A gRNA library targeting transcripts from the whole coding genome of E. coli MG1655 confirms the importance of the transcription threshold in determining immunity and shows that most of the cellular transcripts do not induce cytotoxicity.

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A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13 [Genome wide screen]

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

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

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A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13 [RNA-seq]

Project description:A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13 [RNA-seq]

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A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13 [Genome wide screen]

Project description:A target expression threshold dictates invader defense and autoimmunity by CRISPR-Cas13 [Genome wide screen]

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Intrinsic RNA targeting constrains the utility of CRISPR-Cas13 systems

Project description:This SuperSeries is composed of the SubSeries listed below.

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RNA targeting with CRISPR-Cas13.

Project description:RNA has important and diverse roles in biology, but molecular tools to manipulate and measure it are limited. For example, RNA interference can efficiently knockdown RNAs, but it is prone to off-target effects, and visualizing RNAs typically relies on the introduction of exogenous tags. Here we demonstrate that the class 2 type VI RNA-guided RNA-targeting CRISPR-Cas effector Cas13a (previously known as C2c2) can be engineered for mammalian cell RNA knockdown and binding. After initial screening of 15 orthologues, we identified Cas13a from Leptotrichia wadei (LwaCas13a) as the most effective in an interference assay in Escherichia coli. LwaCas13a can be heterologously expressed in mammalian and plant cells for targeted knockdown of either reporter or endogenous transcripts with comparable levels of knockdown as RNA interference and improved specificity. Catalytically inactive LwaCas13a maintains targeted RNA binding activity, which we leveraged for programmable tracking of transcripts in live cells. Our results establish CRISPR-Cas13a as a flexible platform for studying RNA in mammalian cells and therapeutic development.

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Wound induced small-peptide mediated signalling cascade dictates growth vs defense decision in rice

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