Biology subjects

Labaj, J.

Publications and source records attributed to Labaj, J..

3 recordsLinked to original sources

bioRxiv2026

Rhomboid protease RHBDL2 is a calcium-activated suppressor of EGFR signalling in keratinocytes.

Signalling via the epidermal growth factor receptor (EGFR) is indispensable for morphogenesis and tissue homeostasis. It is activated by extracellular ligands, typically released from transmembrane precursors by proteolysis. Ligand shedding activity is provided by the conserved rhomboid intramembrane serine proteases in Drosophila, but by the unrelated ADAM family metalloproteases in mammals, leaving the functions of mammalian non-mitochondrial rhomboids underexplored. Using quantitative proteomics, we show that EGFR is the main endogenous substrate of the human rhomboid protease RHBDL2 in keratinocytes. By shedding the EGFR ectodomain, thus producing a decoy receptor, RHBDL2 suppresses EGFR signalling, limiting cell migration and invasion. Conspicuously, RHBDL2 activity is upregulated by elevated intracellular calcium concentration, a condition typical for keratinocyte differentiation. These effects are recapitulated in primary human keratinocytes, and human skin equivalents deficient in RHBDL2 display incomplete differentiation and are morphologically disordered compared to wild type cells. We propose that context-specific fine-tuning of EGFR signalling and sensitivity to cross-talk from other signalling pathways could be important and hitherto overlooked roles of rhomboid proteases in mammals.

cell biology↗

bioRxiv2025

IFNG-producing self-reactive CD4+ T cells drive autoimmune adrenalitis in a mouse model of Addison's disease

Autoimmune Addisons disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of Experimental Autoimmune Adrenalitis (EAA) that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFNG produced by self-reactive CD4 T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFNG as a central effector of autoimmune adrenalitis and suggest that targeting the IFNG pathway may represent a potential therapeutic strategy for AD. SignificanceAddisons disease (AD) is a rare autoimmune disorder that destroys the adrenal cortex, yet its underlying mechanisms remain unknown. We developed a mouse model of Experimental Autoimmune Adrenalitis (EAA) that mirrors the hormonal and immunological features of AD. Our study reveals that IFNG-producing CD4 T cells drive adrenal inflammation and dysfunction, identifying IFNG as a key pathogenic factor and a potential therapeutic target.

immunology↗

bioRxiv2025

FAM83H regulates postnatal T cell development through thymic stroma organization

Family of Sequence Similarity 83H (FAM83H/ SACK1H) is primarily expressed in epithelial cells, where it interacts with casein kinase 1 (CK1) and keratins to regulate cytoskeletal organization, cell proliferation, and vesicular trafficking. Mutations in FAM83H are known to cause amelogenesis imperfecta, highlighting its critical role in enamel formation. We generated Fam83h-deficient mice (Fam83hem2(IMPC)Ccpcz, Fam83h-/-) and mice lacking a part of the N-terminal CK1-binding domain (Fam83h{Delta}87/{Delta}87). Consistent with other Fam83h-deficient models, these mice are subviable, smaller in size, and exhibit a sparse, scruffy coat, scaly skin, general weakness, and hypoactivity. Notably, both strains show impaired lymphoid cell development in early postnatal life. In the thymus, Fam83h expression is confined to thymic epithelial cells (TECs), and its deficiency in stromal cells results in disrupted thymic architecture and severe block in the expansion of DN3 (double-negative stage 3) T cells, ultimately leading to insufficient T cell production. Single-cell transcriptomic analysis reveals that Fam83h-/- cortical TECs (cTECs) express reduced levels of the TEC master regulator Foxn1, and its multiple downstream target genes, suggesting a critical role for FAM83H likely in coordination with CK1in cTEC maturation. HighlightsFam83h-deficient mice exhibit multiple epithelial defects, but no obvious enamel defects Fam83h deficiency disrupts lymphocyte development Fam83h deficiency impairs thymic epithelial cell maturation and thymus function

immunology↗