Biology subjects

Lenggenhager, D.

Publications and source records attributed to Lenggenhager, D..

2 recordsLinked to original sources

bioRxiv2023

A HEV ORF2 protein-mediated mechanism of hepatitis E associated kidney disease.

Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN developed in parallel with increasing glomerular deposition of a noninfectious form of HEV open reading frame 2 (ORF2, capsid) protein secreted in excess. HEV particles or RNA, however, were not detectable. Patients with acute hepatitis E displayed similar but less pronounced deposits. Our results elucidate an immunologic mechanism by which this hepatotropic virus causes variable renal manifestations and establish a link between the HEV ORF2 protein and hepatitis E-associated GN. They directly provide a tool for etiology-based diagnosis of HEV-associated GN as a distinct entity and suggest therapeutic implications.

pathology↗

bioRxiv2020

SF3B1 promotes tumor malignancy through splicing-independent co-activation of HIF1α

Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a positive correlation between expression levels of wildtype SF3B1 and tumor malignancy, but underlying mechanisms remain elusive. Here, we report that SF3B1 acts as an activator of HIF signaling through a splicing-independent mechanism. We demonstrate that SF3B1 forms a heterotrimer with HIF1 and HIF1{beta}, facilitating binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. We further validate the relevance of this mechanism for tumor progression. Monoallelic deletion of Sf3b1 impedes formation and progression of hypoxic pancreatic cancer via impaired HIF signaling, but is well tolerated in normoxic chromophobe renal cell carcinoma. Our work uncovers an essential role of SF3B1 in HIF1 signaling, providing a causal link between high SF3B1 expression and aggressiveness of solid tumors.

cell biology↗