Biology subjects

Bolech, E.

Publications and source records attributed to Bolech, E..

3 recordsLinked to original sources

bioRxiv2026

Adaptive immunity is dispensable for salamander appendage regeneration

Complex multi-tissue regeneration capacity varies across vertebrates. Mammals are amongst the least regenerative species, while salamanders can regenerate complex tissues such as limbs and tails throughout life. Previous studies have shown that innate and adaptive immune cells are present during salamander limb regeneration. While innate immune cells have been shown to promote limb regeneration, it is unknown whether adaptive immunity is responsive to amputation or plays a role in appendage regeneration. Here we show that during limb regeneration in axolotls, the immune response is characterized by a coordinated immunoregulatory signature including the downregulation of antigen presentation, cytokine secretion, and T cell activation. We corroborate this transcriptomic data in vivo using skin allografts in newts and define the blastema as an immunosuppressed niche. To test the role of adaptive immune cells in regeneration, we generated Recombination activating gene 1 deficient (Rag1-/-) newts. Rag1-/- newts lack antigen receptor recombination and show a marked reduction of adaptive immune cells. We find that Rag1-/- newts do not reject allografts, confirming their functional immunodeficiency. Finally, we demonstrate that both larval and adult newts regenerate appendages in the absence of adaptive immunity. Our work demonstrates that the adaptive arm of the immune system is not required for appendage regeneration and establishes an important model for novel experimental approaches in comparative immunology and regenerative biology.

immunology↗

bioRxiv2025

IRF2 degradation tunes the innate immune response

The transcription factor IRF2 protects against skin inflammation in mice and humans but, paradoxically, promotes pyroptosis by inducing Gsdmd. How IRF2 activates some proinflammatory genes, but suppresses others is unclear. We show that skin inflammation in Irf2-deficient mice is driven by IRF1 activation of interferon-stimulated genes (ISGs). Chromatin profiling revealed that IRF1 and IRF2 occupy the same ISG regulatory sites, but as a weaker transcriptional activator, IRF2 limited ISG transcription by IRF1. Toll-like receptor signaling favored IRF1-driven transcription by inducing Irf1. In addition, IRF1 recruited the ubiquitin ligase SPOP to ISG sites, resulting in proteasomal degradation of IRF2. This shift from IRF2 to IRF1 occupancy enhanced ISG transcription. Collectively, these findings define a hierarchical transcriptional circuit in which IRF2 limits IRF1 activity under homeostatic conditions but is displaced during an immune response, allowing IRF1-dependent gene programs central to innate immunity and autoinflammation.

immunology↗

bioRxiv2025

The regulation of Protein Phosphatase 4 by FBXO42 is required for cancer cell survival.

FBXO42 is a poorly characterized F-box protein that is essential in 15% of cancer cell lines from diverse tissue types. FBXO42 has been implicated in the regulation of mitosis and p53 signaling. High-throughput approaches indicate that FBXO42 function correlates with that of CCDC6, and that the two proteins interact physically, but the relationship between these proteins is not understood. Through a genome-wide CRISPR knockout screen, we found that mutation of FBXO42 is synthetically lethal with mutations in the {gamma}- tubulin ring complex proteins MZT1 and MZT2B, suggesting that cells with centrosome and/or mitotic spindle assembly dysfunction are more sensitive to FBXO42 loss. Furthermore, we found that FBXO42 and CCDC6 contribute to p53 activation in response to centrosome depletion. Using mass spectrometry-based proteomics, we found that FBXO42 binds, is required for the ubiquitination of, and negatively regulates the expression of PPP4C (protein phosphatase 4 catalytic subunit). FBXO42s interaction with PPP4C was independent of CCDC6. Similarly, we found that CCDC6 physically interacts with PPP4C independently of FBXO42 and does not affect PPP4C ubiquitination. Knockdown of PPP4C reduced FBXO42-CCDC6 interactions, suggesting that FBXO42 and CCDC6 may bind to and regulate PPP4C through separate mechanisms. Using gene knockdown rescue experiments, we confirmed that aberrant expression of PPP4C is a major driver of cell death in an FBXO42-essential Neuroblastoma cell line. These findings shed light on the function of two poorly understood proteins in regulating PP4 activity, p53 signaling, mitosis and cancer cell survival. A better understanding of FBXO42 and CCDC6 could inform the development of targeted cancer therapeutics.

cell biology↗