E3 ubiquitin ligase SKP2 limits autophagosome formation during Staphylococcus aureus infection

TL;DR

This study shows that the protein SKP2 helps control autophagy during Staphylococcus aureus infection, limiting the bacteria's ability to survive inside host cells.

Contribution

The study reveals a novel role for SKP2 in modulating autophagosome formation during S. aureus infection.

Findings

SKP2 abundance increases during S. aureus infection due to acetylation-induced stabilization and cytoplasmic translocation.

SKP2 modulates autophagy induction, with its downregulation increasing intracellular S. aureus survival.

SKP2 overexpression reduces autophagy markers and intracellular bacteria levels.

Abstract

Ubiquitination is a posttranslational modification that affects protein function, stability, and localization and is thereby balancing protein homeostasis. During infection, ubiquitination is crucial in regulating host cell signaling pathways in pathogen recognition, clearance and mounting an efficient immune response. S. aureus is an opportunistic pathogen that is able to invade and multiply within both phagocytic and non-phagocytic mammalian cells depending on virulence factor expression of the respective S. aureus strain. Selective autophagy serves as a host defense mechanism to combat intracellular bacterial persistence by targeting and degrading intracellular pathogens. However, S. aureus can subvert autophagosomal degradation and exploit these organelles for intracellular replication.

We examined the role of the E3 ligase S-phase kinase-associated protein 2 (SKP2), a component of the SKP1-Cullin1-F-box (SCF) – complex, during S. aureus infection in alveolar epithelial and in macrophage-like cells. Upon S. aureus infection, we demonstrate increased SKP2 abundance through acetylation-induced stabilization and translocation into the cytoplasm. Cytoplasmic SKP2 modulated autophagy induction. By downregulation of SKP2, the level of the autophagy marker LC3-II was elevated which was accompanied by increased survival of intracellular S. aureus. Conversely, SKP2 overexpression in host cells reduced LC3-II levels followed by reduced intracellular bacteria.

These findings underscore that SKP2 is an important regulator of autophagosome formation, preventing excessive autophagy from being exploited by S. aureus. In conclusion, our findings reveal novel molecular mechanisms involved in the interaction between host cells and S. aureus providing potential approaches for targeted therapeutic intervention.

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