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Microbes & Immunity PTMs in Sepsis: Mechanisms and therapy

4.1. NLRP3 inflammasome TRIM family, a RING-type E3 ligases subfamily, exhibits
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The NLRP3 inflammasome, a multiprotein complex, dual role of cell death regulation in sepsis. TRIM21
is crucially regulated by ubiquitination in terms of its mediates OAS3 K48-linked polyubiquitination in lung
degradation or activation. 71,72 RING-type E3 ligases epithelial cells, inhibiting apoptosis, thus attenuating
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Cbl-b and RNF125 prevent sepsis by targeting NLRP3 sepsis-induced ALI. It also promotes interferon regulatory
for K63- and K48-linked polyubiquitination, inhibiting factor 1 (IRF1) ubiquitination, reducing IRF1 enrichment,
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NLRP3 inflammasome activation. β-TrCP1, another E3 further improving sepsis-induced ALI. However,
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ubiquitin ligase, promotes NLRP3 degradation through TRIM31 activates the NF-κB pathway by binding to TAK1
and enhancing its ubiquitination, inducing cardiomyocyte
K27-linked ubiquitination, while the transcriptional apoptosis and a “pro-injury” phenotype in sepsis. 85
coactivator yes-associated protein (YAP) stabilizes
NLRP3 by blocking its interaction with β-TrCP1. These findings highlight the therapeutic potential of
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Conversely, the cullin-RING-type E3 ligase KBTBD7 modulating E3 ligase networks – particularly through small-
promotes NLRP3 activation and pro-inflammatory molecule compounds such as YL-109 and samotolisib – to
factors release by ubiquitinating and degrading the reprogram programmed cell death pathways and improve
transcription factor KLF15, exacerbating brain injury sepsis outcomes.
in sepsis. Furthermore, heat shock protein family A
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member 8 (HSPA8) inhibition promotes the E3 ligase 5. SUMOylation and sepsis
SKP2 degradation, attenuating NLRP3 ubiquitination, Small ubiquitin-like modifier (SUMO), a protein containing
thereby exacerbating pyroptosis and sepsis-induced ~100 amino acids, is covalently attached to lysine residues
ALI. Tissue inhibitor of metalloproteinase 2 (TIMP2) of target proteins through a three-step enzymatic cascade
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exerts a renoprotective role in sepsis-associated AKI by mediated by E1, E2 (UBC9), and E3 ligases. This process,
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enhancing the E3 ligase MARCH7-mediated NLRP3 known as SUMOylation, participates in regulating
ubiquitination degradation and attenuating downstream diverse biological processes, including cell signaling, gene
pyroptosis. 77 transcription, cell proliferation, and apoptosis. 87
These findings highlight the therapeutic potential of In sepsis, SUMOylation plays a critical role in
targeting NLRP3 ubiquitination in sepsis. Newly identified modulating inflammation and immune homeostasis.
regulators such as YAP, KLF15, HSPA8, and TIMP2 offer Ubiquitin-conjugating enzyme 9 (UBC9), the sole
novel avenues for therapeutic intervention by modulating E2 ligase for SUMOylation, its deficiency leads to
NLRP3 degradation and activation. dendritic cell hypermaturation, aberrant release of
IL-18/IL-1β and enhances T cell activation, increasing
4.2. Programmed cell death
mortality in septic mice by enhancing, which indicating
Sepsis induces programmed cell death, a process a protective role for SUMOylation in suppressing
dynamically regulated by ubiquitination. RING-type E3 excessive inflammation. SUMO can competitively
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ligase FBXW7 promotes alveolar epithelial cells ferroptosis bind to the same site on IκBα as ubiquitin, inhibiting its
and aggravates sepsis-induced ALI by mediating AUF1 ubiquitination and degradation, thus blocking NF-κB
ubiquitination and degradation. Conversely, HECT- nuclear translocation and downstream pro-inflammatory
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type E3 ligase WWP2 inhibits oxidative stress and factor transcription. SUMOylation deficiency abolishes
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ferroptosis in cardiomyocytes by promoting long-chain this inhibition, resulting in abnormal NF-κB-dependent
acyl CoA synthetase 4 (FACL4) ubiquitination, improving inflammatory factors and type I interferon secretion,
myocardial injury and cardiac function in sepsis. In potentially by regulating interferon-β (Ifnb1) expression
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pyroptosis regulation, CHIP (a chaperone-dependent and suppressing unanticipated amplification of TLR
E3 ligase) inhibits NLRP3 activation and pyroptosis by signaling. Macrophages are important immune cells,
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promoting KPNA2 poly-ubiquitination, thus alleviating with a significant impact on immune homeostasis and
sepsis-induced cardiac dysfunction. YL-109, a small inflammatory processes in sepsis. SUMO-specific
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molecule compound that upregulated CHIP expression, protease 1 (SENP1) regulates transcription factor KLF4
demonstrates therapeutic potential by inhibiting this activity through deSUMOylation. As a key regulator
pathway in various tissues, improving septic multi-organ of macrophage polarization, KLF4 upon SENP1-
damage. Similarly, samotolisib, the PI3K/mTOR pathway mediated deSUMOylation enhances NF-κB signaling,
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inhibitor, activates HECT-type E3 ligase Nedd4, inducing driving M1 macrophage polarization and exacerbating
caspase-11 ubiquitination, thereby specifically blocking inflammation. SENP1 also promotes Sp3 expression
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hepatocyte pyroptosis and improving ALI in sepsis. The through deSUMOylation and interaction with NF-κB,
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Volume 2 Issue 3 (2025) 5 doi: 10.36922/MI025090016