Biology subjects

Tsamouri, L. P.

Publications and source records attributed to Tsamouri, L. P..

3 recordsLinked to original sources

bioRxiv2026

Oxidized TRX1 and DPP8/9 stabilize the MIA40-AIFM1 complex during intrinsic apoptosis

Mammalian cells execute diverse death programs with distinct immunological consequences. Mitochondrial outer membrane permeabilization (MOMP) drives typically immunologically silent intrinsic apoptosis by releasing cytochrome c and other proapoptotic proteins into the cytosol. Here, we show that MOMP also engages two established repressors of the pyroptosis-inducing NLRP1 inflammasome, oxidized thioredoxin-1 (oxTRX1) and catalytically active DPP8/9, in a coordinated redox and proteostasis program. Immediately after MOMP, oxTRX1 forms a disulfide with MIA40 Cys4 at the MIA40-AIFM1 interface. Subsequently, DPP8/9 cleave AK2, targeting this competing AIFM1 ligand for degradation. Biochemical reconstitution and cryo-EM reveal that oxTRX1 promotes AIFM1 dimerization and preferentially stabilizes MIA40-AIFM1 over AK2-AIFM1. Thus, redox-dependent complex assembly and selective proteolysis converge to favor MIA40-bound AIFM1 after MOMP. These findings suggest how post-MOMP remodeling could reinforce NLRP1 restraint during apoptosis and how disruption of this program could trigger pyroptosis.

cell biology↗

bioRxiv2026

Distinct lipid transport proteins are regulated by innate immune stimuli

Lipid transport plays a critical role in the distribution of lipids across subcellular compartments. This is pivotal during infection and other stress stimuli that increase metabolic demands. While lipid biosynthesis is regulated by immune stimuli, whether immune signalling also influences lipid transport mechanisms remains unexplored. Here, we demonstrate that TLR signalling impacts the gene expression of lipid transport proteins in human monocytic THP-1 cell line and compare it to the expression in primary bone marrow-derived mouse macrophages. Our data demonstrates that TLR4 signalling selectively modulates the expression of oxysterol-binding protein-related proteins (ORPs), a key family of proteins that transport lipids between organelles. Remarkably, TLR4 activation led to the downregulation of several ORP family members in human THP1-derived macrophages. However, this response was less profound in mouse macrophages. In contrast, the expression of steroidogenic acute regulatory domain (STARD) proteins, many of which transport lipids between mitochondria and other compartments, remained broadly unaffected. Moreover, IFNG, a cytokine that plays a key role in the immune response, did not considerably impact human ORP or STARD expression levels, either alone or in combination with LPS. Together, these results reveal that TLR signalling exerts selective and critical control over lipid trafficking pathways with important species-specific differences. These findings provide new insights into the crosstalk between immune signalling and lipid metabolism, which may offer novel targets to treat diseases characterized by dysregulated lipid pathways.

immunology↗

bioRxiv2023

The interaction between NLRP1 and oxidized TRX1 involves a transient disulfide bond

NLRP1 is an innate immune receptor that detects pathogen-associated signals, assembles into a multiprotein structure called an inflammasome, and triggers a proinflammatory form of cell death called pyroptosis. We previously discovered that the oxidized, but not the reduced, form of thioredoxin-1 directly binds to NLRP1 and represses inflammasome formation. However, the molecular basis for NLRP1s selective association with only the oxidized form of TRX1 has not yet been established. Here, we leveraged Alphafold-Multimer, site-directed mutagenesis, thiol-trapping experiments, and mass spectrometry to reveal that a specific cysteine residue (C427 in humans) on NLRP1 forms a transient disulfide bond with oxidized TRX1. Overall, this work demonstrates how NLRP1 monitors the cellular redox state, further illuminating an unexpected connection between the intracellular redox potential and the innate immune system.

immunology↗