FBXO11 governs macrophage cell death and inflammation in response to bacterial toxins

Abstract

Staphylococcus aureuscauses severe infections such as pneumonia and sepsis depending on the pore-forming toxin Panton–Valentine leukocidin (PVL). PVL kills and induces inflammation in macrophages and other myeloid cells by interacting with the human cell surface receptor, complement 5a receptor 1 (C5aR1). C5aR1 expression is tighly regulated and may thus modulate PVL activity, although the mechanisms involved remain incompletely understood. Here, we used a genome-wide CRISPR/Cas9 screen and identified F-box protein 11 (FBXO11), an E3 ubiquitin ligase complex member, to promote PVL toxicity. Genetic deletion of FBXO11 reduced the expression of C5aR1 at the mRNA level, whereas ectopic expression of C5aR1 in FBXO11−/−macrophages, or priming with LPS, restored C5aR1 expression and thereby PVL toxicity. In addition to promoting PVL-mediated killing, FBXO11 dampens secretion of IL-1β after NLRP3 activation in response to bacterial toxins by reducing mRNA levels in a BCL-6–dependent and BCL-6–independent manner. Overall, these findings highlight that FBXO11 regulates C5aR1 and IL-1β expression and controls macrophage cell death and inflammation following PVL exposure.

High-throughput CRISPR technology: a novel horizon for solid organ transplantation

“…It is a suspension cell line and suitable for transfection or infection experiments. In 2023, Naderer et al conducted a FACS-based genome-wide CRISPR/Cas9 screen in the THP-1 cell line to explore the mechanism between Panton-Valentine leukocidin (PVL) and complement C5a receptor 1 (C5aR1) (107). FBXO11 was identified as the potential target in macrophages for inflammation.…”

Gaining New Insights into Fundamental Biological Pathways by Bacterial Toxin-Based Genetic Screens

“…Another recently reported CRISPR screen for PVL by Jeon et al was conducted in differentiated macrophages [ 156 ]. Besides the known PVL receptor C5AR1 , FBXO11 (F-box protein 11) was also enriched in the screen.…”

“…Jeon et al found that FBXO11 -knockout cells exhibited reduced transcription of C5AR1 that could be restored by lipopolysaccharide (LPS) priming. FBXO11 was further demonstrated to regulate the inflammasome pathway and the expression of IL-1β through BCL6-dependent and BCL6-independent transcriptional regulations [ 156 ].…”