Role of ubiquitin-associated lncRNAs in myeloid immune imbalances during sepsis

• Applicant: Professor Dr. Leon Schulte
• Subject Area: Immunology ; Clinical Immunology and Allergology ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574426686

Sepsis is a life-threatening condition caused by a derailed systemic host response to infection and remains a major healthcare challenge due to complex pathophysiology and limited therapeutic options. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression, yet research into their roles in immune-dysfunctions in humans is still in its infancy. During our preliminary work, we were able to identify dozens of lncRNAs that are significantly upregulated in peripheral blood leukocytes during sepsis. Several of these lncRNAs co-precipitate with ubiquitin – an essential factor in intracellular immune signaling. For the sepsis-induced lnRNAs MaIL1, PELATON and NORAD, we were able to identify specific ubiquitin-associated protein interactors that could be crucial for the role of these lncRNAs in the immune system. The aim of this project is to comprehensively determine the contribution of ubiquitin-associated lncRNAs to immune modulation during sepsis. By combining basic and clinical research methodologies, including single-cell and nanopore sequencing, RNA antisense purification, PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation), and high-resolution microscopy, we aim to provide unparalleled insights into the role of lncRNAs in sepsis. WP1 focuses on the cell type specificity and splice-structure of sepsis-associated lncRNAs, particularly in myeloid cells. The aim of WP2 is to identify protein interactors of sepsis-relevant ubiquitin-bound lncRNAs and to map their binding sites on RNA. WP3 will elucidate the specific modes of action of lncRNAs (including MaIL1, PELATON and NORAD) during ubiquitin-dependent regulation of immune pathways with relevance to sepsis endotypes. Finally, WP4 aims to determine the clinical relevance of our findings and to narrow down the potential of lncRNAs examined in WP2-3 as biomarkers and therapeutic targets for severity assessment and treatment of sepsis and related conditions. We believe that with this research project we will make significant progress in understanding the role of RNA in the ubiquitin system and in sepsis pathogenesis. By elucidating novel RNA mechanisms in the systemic host response to infection, our project could open new avenues for targeted therapies and clinical management of patients with sepsis and related life-threatening immune imbalances.

• DFG Programme: Research Grants