Mycobacterial phage TM4 requires a eukaryotic-like Ser/Thr protein kinase to silence and escape anti-phage immunity

• Published in: Cell host & microbe Vol. 31; no. 9; pp. 1469 - 1480.e4
• Main Authors: Li, Xiaohui, Long, Xiating, Chen, Liu, Guo, Xiao, Lu, Lining, Hu, Lihua, He, Zheng-Guo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.09.2023
• Subjects: anti-phage defense; gene island; M. smegmatis; phage; Ser/Thr protein kinase; anti-phage defense; phage; M. smegmatis; gene island; Ser/Thr protein kinase
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2023.07.005

In eukaryotic cells, serine/threonine protein kinases (StpKs) play important roles in limiting viral infections. StpKs are commonly activated upon infections, inhibiting the expression of genes central for viral replication. Here, we report that a eukaryotic-like StpK7 encoded by MSMEG_1200 in M. smegmatis is required for mycobacteriophage TM4 to escape bacterial defense. stpK7 is located within a gene island, MSMEG_1191-MSMEG_1200, containing multiple anti-phage genes resembling the BREX (bacteriophage exclusion) phage-resistance system. StpK7 negatively regulates the expression of this gene island. Following phage TM4 infection, StpK7 is induced, directly phosphorylating the transcriptional regulator MSMEG_1198 and inhibiting its positive regulatory activity, thus reducing the expression of multiple downstream genes in the BREX-like gene island. Further analysis showed that genes within this anti-phage island critically regulate mycobacterial lipid hemostasis and phage adsorption. Collectively, this work characterizes a regulatory network driven by StpK7, which is utilized by phage TM4 to escape from the host defense against mycobacteria. [Display omitted] •M. smegmatis has a typical eukaryotic-like Ser/Thr protein kinase•Mycobacteriophage TM4 uses StpK7 to escape from a host bacterial defense system•stpK7 is located in a gene island containing multiple BREX-like anti-phage genes•StpK7 reduces gene island expression to enhance phage absorption and replication Li et al. characterize a eukaryotic-like Ser/Thr protein kinase StpK7 in M. smegmatis, which is utilized by mycobacteriophage TM4 to escape host defense mediated by a BREX-like anti-phage gene island. Their study provides key insights into the role and regulatory pathway of StpKs in mycobacteriophage-host interactions.