Csx28 is a membrane pore that enhances CRISPR-Cas13b–dependent antiphage defense
Open accessPublished version of a preprint
Abstract
Type VI CRISPR-Cas systems use RNA-guided ribonuclease (RNase) Cas13 to defend bacteria against viruses, and some of these systems encode putative membrane proteins that have unclear roles in Cas13-mediated defense. We show that Csx28, of type VI-B2 systems, is a transmembrane protein that assists to slow cellular metabolism upon viral infection, increasing antiviral defense. High-resolution cryo–electron microscopy reveals that Csx28 forms an octameric pore-like structure. These Csx28 pores localize to the inner membrane in vivo. Csx28’s antiviral activity in vivo requires sequence-specific cleavage of viral messenger RNAs by Cas13b, which subsequently results in membrane depolarization, slowed metabolism, and inhibition of sustained viral infection. Our work suggests a mechanism by which Csx28 acts as a downstream, Cas13b-dependent effector protein that uses membrane perturbation as an antiviral defense strategy.
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- Authors
- VanderWal, A. R., Park, J.-U., Polevoda, B., Nicosia, J. K., Molina Vargas, A. M., Kellogg, E. H., & O’Connell, M. R.
- Affiliations
- University of Rochester Medicine (US)
- Cornell University (US)
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA.
- Corresponding author
- O’Connell, Mitchell R.
- ORCID
- Venue
- Science
- Published
- 2023-04-28
- Volume
- 380
- Issue
- 6643
- Pages
- 410-415
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC10228660
- OpenAlex
- W4367173663
- Cited by
- 55
- References
- 6
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 8 · 2023: 9 · 2022: 12 · 2021: 2
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (1719875)
- University of Rochester (T90 DE021985)
- Centre International de Recherche sur le Cancer
- National Institutes of Health (1s10od021489-01a1, DMR-1719875, MCB200090)
- Cornell Center for Materials Research (DMR‐1719875, 1719875)
- Medical Center, University of Rochester
- Materials Research Science and Engineering Center, Harvard University (DMR- 1719875, 1719875)
- National Institute of General Medical Sciences (T32GM118283, R01GM144566, T32GM145461, T32GM135134, R35GM133462)
- National Institute of Dental and Craniofacial Research (T90DE021985)
- Division of Materials Research (DMR-1719875, 1719875)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- anti-phage defense, membrane pores, transmembrane proteins, membrane depolarization, cellular metabolism, inner membrane, antiviral defense, effector proteins
- MeSH terms
- Bacterial Proteins, Bacteriophages, Endodeoxyribonucleases, Escherichia coli, Membrane Proteins, Bacteriophage lambda, RNA, Viral, Prevotella, Cryoelectron Microscopy, RNA Cleavage, CRISPR-Cas Systems, CRISPR-Associated Proteins
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