Receptors of second messengers involved in anti-phage defense
Date
2023
Authors
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Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Cyclic nucleotide-based second messengers (cNSMs) play a crucial role in regulating diverse cellular functions. In bacterial systems, scientific understanding was previously dominated by purine derivatives like cyclic di-AMP, cyclic di-GMP, and cyclic GMP-AMP. However, recent discoveries have introduced novel purine-based cyclic trinucleotides and a range of pyrimidine-containing cNSMs. These newfound players orchestrate bacterial anti-phage defense systems such as CBASS and Pycsar. These systems, encoded in conserved operons distributed widely in the bacterial kingdom, underscore their importance in mediating immune responses against phages. Despite their prevalence, the underlying mechanisms of these defense these systems remain mysterious, primarily due to lack of confirmed protein receptors for pyrimidine-containing cNSMs. Cyclic UMP, cyclic CMP, cyclic UMP-AMP, and cyclic AMP-AMP-GMP each have single identified protein receptor, leaving other pyrimidine-containing cNSMs without confirmed binding partners. ☐ To unravel the functional mysteries of these novel cNSMs, a series of pulldown assays used cNSMs as "bait" molecules to extract potential receptors from cell lysates. A comparative analysis with control pulldowns revealed that candidate receptors from cNSM-immobilized pulldowns are predominantly involved in metabolic processes. Furthermore, a comprehensive domain analysis uncovered a recurring pattern of domains associated with proteins integral to cellular metabolism among the identified receptor candidates. ☐ While further binding assays using purified proteins is imperative to confirm the legitimacy of these candidates as true receptors, the preliminary findings suggest a broader functional landscape for these novel cNSMs in bacterial physiology. Beyond their anticipated roles in anti-phage defense, these cNSMs may wield multifaceted functions within bacterial systems, elevating their significance in microbial biology.
Description
Keywords
Cellular functions, Bacterial systems, Purine derivatives, Cellular metabolism