Biology subjects

Chrusciel, E.

Publications and source records attributed to Chrusciel, E..

3 recordsLinked to original sources

bioRxiv2026

STAT3 dual role in sex-biased and differentiation-gated interferon gamma memory

The innate immune system possesses a unique form of memory, known as trained immunity. An initial stimulus induces cellular reprogramming for a non-specific amplified response to a subsequent challenge. This process can be achieved through gene priming, where exposure to a specific cue sensitizes future gene expression. Interferon-gamma (IFN{gamma}) memory is a specialized form of priming, where both the initial and recall signals are mediated by the same IFN{gamma} cytokine. The mechanisms governing IFN{gamma} memory in humans remain poorly understood. We investigated the mechanisms governing IFN{gamma} memory and characterized it in human primary macrophages. We discovered a dual role for the STAT3 transcription factor in IFN{gamma} memory. It acts as a repressor of memory establishment by indirectly inhibiting STAT1 Ser727 phosphorylation, while also being required for memory recall. Furthermore, we demonstrated that IFN{gamma} memory is sex-biased, with males exhibiting a more pronounced effect characterized by reduced variability in gene expression upon re-exposure to IFN{gamma}. This defines IFN{gamma} recall as a function of transcriptional precision. We also identified a novel family of chemokine genes that exhibit IFN{gamma} concentration dependent memory effects. Additionally, we established a model system to study this process and found that memory is critically dependent on the cellular phenotype. Specifically, our results show that for some genes, monocyte-to-macrophage differentiation is necessary, while for others, this differentiation step is sufficient for recall of the previous response. Our findings redefine the IFN{gamma} memory program, establishing it as a sex-biased phenomenon governed by a novel regulatory network involving differentiation and STAT3 function. These insights provide critical context for understanding immune heterogeneity and are essential for the rational design of personalized therapies that harness trained immunity.

molecular biology↗

bioRxiv2022

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

The Major Histocompatibility Complex class I (MHC-I) molecules present antigenic peptides (AP) to CD8+ T cells for self versus non-self recognition. Loading of AP on MHC-I takes place in the endoplasmic reticulum (ER), upon shuttling of cytoplasmic AP substrates to the ER. Understanding of this process has been influenced by the view that MHC-I antigens are produced from the proteasomal degradation of cellular proteins. Recent observations on the intronic and untranslated region-derived peptides as well as on the non-AUG translation products presented on the MHC-I open the possibility that antigenic peptides can derive from pre-spliced mRNAs translated in the nuclear compartment. In this brief report, we show that a fraction of human MHC-I molecules (human leukocyte antigens type A, HLA-A) is present in the nuclei of cells, in the proximity of histone H2B. With this finding, we hope to initiate a new direction of research on the nuclear role of MHC-I and ask whether the loading of antigens can take place in the nuclear compartment.

immunology↗

bioRxiv2022

Keap1-resistant ΔN-Nrf2 isoform does not translocate to the nucleus upon electrophilic stress

The Nrf2 pathway is an essential defense pathway in a cell. It responds to oxidative and electrophilic stress via derepression of Nrf2 from Keap1-Cul3-mediated degradation, accumulation of Nrf2 in the nucleus and transcriptional activation of a number of detoxifying and cell protective Nrf2 target genes. Here we report that normal and cancer cells also express the N-terminally truncated Nrf2 isoform ({Delta}N-Nrf2), which originates from an alternative promoter. Co-immunoprecipitation together with molecular dynamics simulation showed that the binding between {Delta}N-Nrf2 and Keap1 is impaired, resulting in the much higher stability of this form. {Delta}N-Nrf2 is retained in the cytoplasm in response to electrophilic stress, indicating that it does not regulate transcription under the same stress stimuli as the full-length Nrf2. Altogether this data suggests that Nrf2 has other functions in cells than transcriptional activation of genes, which most probably rely on the protein-protein interactions in the cytoplasm. The regulation between these functions takes place on the level of transcription. Significance StatementThis work signifies the importance of alternative transcription in assigning the function to the produced protein. Nrf2 transcripts produced from the second promoter of the Nrf2 gene give rise to the N-terminally truncated Nrf2 form ({Delta}N-Nrf2), which is retained in the cytoplasm upon stress, thus it has a different role in cells than transcriptional regulation. {Delta}N-Nrf2 is resistant to the Keap1-Cul3 degradation pathway and is highly expressed in all tested cell types. This work points to the new, cytoplasmic role of Nrf2 in cells, determined at the level of transcription.

cell biology↗