Functional insights into nucleoside diphosphate kinases encoded by two ndk paralogs in Waddlia chondrophila

Highlights

• W. chondrophila encodes two Ndk paralogs, unlike most Chlamydiota.

• ndk genes are early expressed and protein levels peak during bacterial replication.

• WcNdk1 is inclusion-bound, while WcNdk2 localizes to host cell compartments.

• AZT inhibits bacterial growth and protects host cells from infection-induced death.

• AZT sensitivity is linked to ndk2 presence, implicating WcNdk2 as functional target.

Abstract

The Chlamydiota phylum consists of obligate intracellular bacteria, including well-known pathogens and emerging environmental species, with diverse host ranges and metabolic capabilities. Among these bacteria, the gene which encodes nucleoside diphosphate kinase, ndk is present in variable numbers. While most chlamydial species carry a single paralog of ndk, some species have two paralogs. In Waddlia chondrophila, the two Ndk proteins encoded by ndk paralogs retain conserved kinase motifs but differ in subcellular localization, suggesting divergent functional roles. According to localization studies performed in heterologous expression systems, WcNdk1 is confined to the bacteria-containing vacuole and probably supports nucleotide metabolism, while WcNdk2 localizes to the host nucleus, perinuclear space, and Golgi apparatus, suggesting involvement in host interaction. Azidothymidine (AZT), a known Ndk inhibitor, impaired W. chondrophila growth, potentially through inhibition of WcNdk2. However, the lack of genetic tools currently limits definitive functional conclusions. Our data suggests potential functions for Ndks in W. chondrophila, providing a foundation for future studies on Ndk-mediated interactions between this pathogen and its host, which might possibly be translated into a new therapeutic approach.

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https://www.sciencedirect.com/science/article/pii/S266651742600091X