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Determining changes in the oxidized proteome of human CD8+ T cells with enhancing proteasome activity

ABSTRACT: Chronic T cell receptor (TCR) stimulation, combined with adverse conditions in the tumor microenvironment (TME) such as hypoxia and nutrient deprivation, frequently results in T cell exhaustion. Exhausted T cells (TEX) experience oxidative stress, which causes an accumulation of oxidized proteins within the cells. We hypothesized that oxidized protein formation might exceed proteasomal degradation capacity, leading to their accumulation and impairing TEX cell fitness. By pharmacologically boosting proteasome activity, we decreased the accumulation of oxidized proteins, delaying T exhaustion and enhancing T cell fitness, resulting in superior anti-tumor control.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Mikel Azkargorta

LAB HEAD: Felix Elortza

PROVIDER: PXD070152 | Pride | 2026-03-12

REPOSITORIES: Pride

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			Action	DRS
	250923_250911D_DeBlas_RIME.xlsx	Xlsx
	250925_250911D_DeBlas_1_S1-A10_1_2811.d.zip	Other
	250925_250911D_DeBlas_2_S1-A11_1_2812.d.zip	Other
	250925_250911D_DeBlas_3_S1-A12_1_2813.d.zip	Other
	250925_250911D_DeBlas_4_S1-B1_1_2814.d.zip	Other

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Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases. We collected culture media from differentiated SH-SY5Y cells overexpressing either human a-synuclein (alpha-SCM) or beta-galactosidase (LZCM) and treat these media to primary rat microglia at the concentration of a-synuclein of 1.1M. Transcriptome analyses with microglial cells treated with either aSCM or LZCM at two different time points, 6 h and 24 h.

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Determining changes in the oxidized proteome of human CD8+ T cells with enhancing proteasome activity

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