Browsing by Author "Kuehn, Meta"

Now showing 1 - 3 of 3
  • Thumbnail Image
    ItemOpen Access
    Dynamin-related Irgm proteins modulate LPS-induced caspase-4 activation and septic shock
    (2020) Finethy, Ryan; Dockterman, Jacob; Kutsch, Miriam; Orench-Rivera, Nichole; Wallace, Graham; Piro, Anthony; Luoma, Sarah; Haldar, Arun; Hwang, Seungmin; Martinez, Jennifer; Kuehn, Meta; Taylor, Gregory; Coers, Jörn

    ABSTRACT

    Inflammation associated with gram-negative bacterial infections is often instigated by the bacterial cell wall component lipopolysaccharide (LPS). LPS-induced inflammation and resulting life-threatening sepsis are mediated by the two distinct LPS receptors TLR4 and caspase-4. Whereas the regulation of TLR4 activation by extracellular and phago-endosomal LPS has been studied in great detail, auxiliary host factors that specifically modulate recognition of cytosolic LPS by caspase-4 are largely unknown. This study identifies dynamin-related membrane remodeling proteins belonging to the family of Immunity related GTPases M clade (IRGM) as negative regulators of caspase-4 activation in macrophages. Phagocytes lacking expression of mouse isoform Irgm2 aberrantly activate caspase-4-dependent inflammatory responses when exposed to extracellular LPS, bacterial outer membrane vesicles or gram-negative bacteria. Consequently, Irgm2-deficient mice display increased susceptibility to caspase-4-mediated septic shock in vivo. This Irgm2 phenotype is partly reversed by the simultaneous genetic deletion of the two additional Irgm paralogs Irgm1 and Irgm3, indicating that dysregulated Irgm isoform expression disrupts intracellular LPS processing pathways that limit LPS availability for caspase-4 activation.
  • Thumbnail Image
    ItemOpen Access
    Modulation of Cell Differentiation and Epigenetic Landscape by Methionine Metabolism
    (2024) Sun, Yudong

    Histone modifications are an integral component of epigenetic mechanisms, crucially influencing DNA accessibility and gene expression. These modifications are increasingly recognized as being deeply intertwined with cellular metabolism, particularly through the use of metabolic intermediates as substrates or catalytic cofactors for histone modifiers. This is especially evident in the metabolism of methionine, which significantly affects histone methylation by modulating the availability of substrates for histone methyltransferases. The activities of these enzymes are highly sensitive to substrate concentration due to their unique kinetic properties. Despite some degree of observation and study, the direct impact of methionine availability on specific histone modifications, like H3K36me3, and their ensuing effects on cellular functions have not been extensively explored.

    To address this knowledge gap, I employed a combination of genetic, biochemical, and pharmacological approaches to examine the consequences of methionine restriction on H3K36me3 and its impact on cellular differentiation. This involved characterizing the dynamics, and reversibility of these processes, and identifying the mediating factors between methionine and cellular differentiation. Our findings highlight a significant dependency of myogenic differentiation on methionine and establish the methionine-SAM-SETD2 pathway as a critical component in this process.

    This work provides compelling evidence of a connection between nutrient status and cell-fate determination, potentially mediated by histone status. These insights offer new perspectives on the complex interplay between metabolism and epigenetics, laying the foundation for a more profound understanding of how these processes interconnect to influence cellular fate decisions.

  • Thumbnail Image
    ItemOpen Access
    The inoculum effect and band-pass bacterial response to periodic antibiotic treatment.
    (Mol Syst Biol, 2012) Tan, Cheemeng; Smith, Robert Phillip; Srimani, Jaydeep K; Riccione, Katherine A; Prasada, Sameer; Kuehn, Meta; You, Lingchong
    The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.