A target expression threshold dictates invader defense and prevents autoimmunity by CRISPR-Cas13.
Cell Host Microbe
; 30(8): 1151-1162.e6, 2022 08 10.
Article
en En
| MEDLINE
| ID: mdl-35690065
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Bacteriófagos
/
Sistemas CRISPR-Cas
Idioma:
En
Revista:
Cell Host Microbe
Asunto de la revista:
MICROBIOLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Alemania