Abstract
The nucleolus is a multifunctional structure within the nucleus of eukaryotic cells and is the primary site of ribosome biogenesis. Almost all viruses target and disrupt the nucleolus—a feature exclusive to this pathogen group. Here, using a combination of bio-imaging, genetic and biochemical analyses, we demonstrate that the enteropathogenic E. coli (EPEC) effector protein EspF specifically targets the nucleolus and disrupts a subset of nucleolar factors. Driven by a defined N-terminal nucleolar targeting domain, EspF causes the complete loss from the nucleolus of nucleolin, the most abundant nucleolar protein. We also show that other bacterial species disrupt the nucleolus, dependent on their ability to deliver effector proteins into the host cell. Moreover, we uncover a novel regulatory mechanism whereby nucleolar targeting by EspF is strictly controlled by EPEC's manipulation of host mitochondria. Collectively, this work reveals that the nucleolus may be a common feature of bacterial pathogenesis and demonstrates that a bacterial pathogen has evolved a highly sophisticated mechanism to enable spatio-temporal control over its virulence proteins.
Highlights
Central to the pathogenesis of many viral pathogens is the requirement to target the nucleolus [1], a sub-nuclear structure found in all eukaryotic cells that is the primary site of ribosome biogenesis
We show that EspF, a well-studied effector of enteropathogenic E. coli, targets the host’s nucleolus in both infected and transfected cells and causes extensive nucleolar changes
Only viruses were known to target and disrupt the nucleolus but we show that bacteria other than E. coli disrupt this organelle
Summary
Central to the pathogenesis of many viral pathogens is the requirement to target the nucleolus [1], a sub-nuclear structure found in all eukaryotic cells that is the primary site of ribosome biogenesis. For several decades viruses have been reported to subvert or hijack specific nucleolar proteins by causing their relocalisation from the nucleolus to another subcellular site such as the cytoplasm where they are presumably unable to perform their nucleolar functions [1] Unlike their viral counterparts, no other pathogen group including fungi, protozoa or bacteria are known to target or disrupt the nucleolus, presumably reflecting the viral dependence on the host transcription or translation machinery. Many notorious animal and plant pathogenic bacteria that cause some of our most devastating diseases, possess type three- or type four secretion systems to deliver multiple effector proteins directly into eukaryotic cells - a process that is essential to cause disease [5] These effectors exhibit diverse biochemical activities, subverting many important aspects of host cell physiology and are often highly multifunctional [6,7]. A successful approach in understanding the roles of effectors has been to identify effector families or common host cell targets that may be important across a wide range of bacterial pathogens
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