TY - JOUR
T1 - Antiviral signalling by a cyclic nucleotide activated CRISPR protease
AU - Rouillon, Christophe Marcel Joseph
AU - Schneberger, Niels
AU - Chi, Haotian
AU - Blumenstock, Katja
AU - Da Vela, Stefano
AU - Ackermann, Katrin
AU - Moecking, Jonas
AU - Peter, Martin F.
AU - Boenigk, Wolfgang
AU - Seifert, Reinhard
AU - Bode, Bela Ernest
AU - Schmid-Burgk, Jonathan L.
AU - Svergun, Dmitri
AU - Geyer, Matthias
AU - White, Malcolm
AU - Hageluken, Gregor
N1 - Funding information: M.G. and J.L.S.B. are funded by the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy–EXC2151–390873048. M.F.W. acknowledges a European Research Council Advanced Grant (grant number 101018608) and the China Scholarship Council (REF: 202008420207 to H.C.). G.H. is grateful for funding by the Deutsche Forschungsgemeinschaft (grant number HA6805/6-1).
PY - 2023/2/2
Y1 - 2023/2/2
N2 - CRISPR defence systems such as the well-known DNA-targeting Cas9 and the
RNA-targeting type III systems are widespread in prokaryotes1,2.
The latter orchestrates a complex antiviral response that is initiated
through the synthesis of cyclic oligoadenylates after recognition of
foreign RNA3,4,5. Among the large set of proteins that are linked to type III systems and predicted to bind cyclic oligoadenylates6,7, a CRISPR-associated Lon protease (CalpL) stood out to us. CalpL contains a sensor domain of the SAVED family7
fused to a Lon protease effector domain. However, the mode of action of
this effector is unknown. Here we report the structure and function of
CalpL and show that this soluble protein forms a stable tripartite
complex with two other proteins, CalpT and CalpS, that are encoded on
the same operon. After activation by cyclic tetra-adenylate (cA4),
CalpL oligomerizes and specifically cleaves the MazF homologue CalpT,
which releases the extracytoplasmic function σ factor CalpS from the
complex. Our data provide a direct connection between CRISPR-based
detection of foreign nucleic acids and transcriptional regulation.
Furthermore, the presence of a SAVED domain that binds cyclic
tetra-adenylate in a CRISPR effector reveals a link to the
cyclic-oligonucleotide-based antiphage signalling system.
AB - CRISPR defence systems such as the well-known DNA-targeting Cas9 and the
RNA-targeting type III systems are widespread in prokaryotes1,2.
The latter orchestrates a complex antiviral response that is initiated
through the synthesis of cyclic oligoadenylates after recognition of
foreign RNA3,4,5. Among the large set of proteins that are linked to type III systems and predicted to bind cyclic oligoadenylates6,7, a CRISPR-associated Lon protease (CalpL) stood out to us. CalpL contains a sensor domain of the SAVED family7
fused to a Lon protease effector domain. However, the mode of action of
this effector is unknown. Here we report the structure and function of
CalpL and show that this soluble protein forms a stable tripartite
complex with two other proteins, CalpT and CalpS, that are encoded on
the same operon. After activation by cyclic tetra-adenylate (cA4),
CalpL oligomerizes and specifically cleaves the MazF homologue CalpT,
which releases the extracytoplasmic function σ factor CalpS from the
complex. Our data provide a direct connection between CRISPR-based
detection of foreign nucleic acids and transcriptional regulation.
Furthermore, the presence of a SAVED domain that binds cyclic
tetra-adenylate in a CRISPR effector reveals a link to the
cyclic-oligonucleotide-based antiphage signalling system.
U2 - 10.1038/s41586-022-05571-7
DO - 10.1038/s41586-022-05571-7
M3 - Article
SN - 0028-0836
VL - 614
SP - 168
EP - 174
JO - Nature
JF - Nature
ER -