Biology subjects

Wenzel, D.

Publications and source records attributed to Wenzel, D..

4 recordsLinked to original sources

bioRxiv2024

In-situ architecture of the human prohibitin complex

Prohibitins are a highly conserved family of proteins that have been implicated in a variety of functions including mitochondrial stress signalling and housekeeping, cell cycle progression, apoptosis, lifespan regulation and many others1, 2. The human prohibitins PHB1 and PHB2 have been proposed to act as scaffolds within the mitochondrial inner membrane, but their molecular organisation remained elusive. Using an integrative structural biology approach combining quantitative Western blotting, cryo-electron tomography, subtomogram averaging and molecular modelling, we determined the molecular organisation of the human prohibitin complex within the mitochondrial inner membrane. The proposed bell-shaped structure consists of eleven alternating PHB1 and PHB2 molecules. This study reveals an average of about 43 prohibitin complexes per crista, covering 1-3 % of the cristae membranes. These findings provide a structural basis for understanding the functional contributions of prohibitins to the integrity and spatial organisation of the mitochondrial inner membrane.

cell biology↗

bioRxiv2022

Deficiency in hyaluronan synthase 3 attenuates ruptures in a murine model of abdominal aortic aneurysms by reduced aortic monocyte infiltration

Abdominal aortic aneurysms (AAA) are a common vascular disorder with a high mortality due to the prevalence of aortic ruptures. The underlying pathomechanisms are complex and involve immune cell infiltration and degradation of the vascular extracellular matrix (ECM). Hyaluronan (HA), synthesized at the plasma membrane by three HA synthase isoenzymes (HAS1-3), is not only a major constituent of the ECM but also known to directly affect the phenotype of vascular smooth muscle cells as well as immunological responses. Specifically, the HAS3 isoenzyme has been reported to play a major role in various inflammatory conditions. Therefore, the aim of the present study was to elucidate the role of HAS3-derived HA in the pathogenesis of abdominal aortic aneurysm. To this end, we used a murine model of Angiotensin II (AngII)-induced abdominal aortic aneurysms and dissections (AAAs/AADs) and could demonstrate that genetic depletion of Has3 improves survival in Apoe/Has3 double deficient (Apoe/Has3-DKO) mice via the reduced occurrence of aortic ruptures. Mechanistically, fewer elastica breaks were observed in Apoe/Has3-DKO mice compared to Apoe-KO littermates. This was associated with a decreased infiltration of myeloid immune cells into the vessel wall of Has3-deficient mice while in parallel elevated numbers of circulating leukocytes were detected. RNA seq analysis from aortic tissue pointed towards a disturbed endothelial-myeloid cell communication as a cause for the diminished recruitment of immune cells to the aortic wall. While endothelial cells were unaffected, upregulation of adhesion receptors as well as the HA receptor CD44, known to mediate leukocyte adhesion to the endothelium, was blunted in monocytes from Apoe/Has3-DKO mice in response to AngII treatment. These findings underline the pivotal detrimental role of monocytes HAS3-dependent pericellular HA matrix for an exaggerated immune cell recruitment to inflammatory foci giving here rise for an increased incidence of ruptured aortic aneurysms.

immunology↗

bioRxiv2022

Inhibition of myeloperoxidase prevents thoracic aortic aneurysm formation in Marfan mice

Marfan syndrome (MFS) is the most prevalent inherited connective tissue disorder, still remains uncurable, and is characterized by high mortality at early age driven by dissection and rupture of thoracic aortic aneurysms. MFS is caused by mutations in the fibrillin-1 gene and aberrant TGF{beta} signaling. Here we addressed whether myeloperoxidase (MPO), a leukocyte derived enzyme with potent matrix modulating properties also influences the aortic phenotype in MFS. MFS patients displayed increased circulating MPO levels compared to controls as well as marked aortic MPO deposition. In an MFS mouse model, MPO induced inflammatory endothelial activation and endothelial to mesenchymal transition which triggered aortic leukocyte recruitment. Moreover, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitration of proteins within the vascular wall. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and - in the absence of any pharmacological treatment so far in this disease - a first anti-inflammatory target to modulate disease progression.

immunology↗

bioRxiv2018

The ESCRT-III proteins IST1 and CHMP1B assemble around nucleic acids

ESCRT-III proteins can promote inside-out or outside-in membrane tubulation and fission. In addition, several observations suggest that ESCRT factors may also associate with nucleic acids during development, different stages of the cell cycle, and during retro-transposition of parasitic nucleic acids like LINE1 elements. Two ESCRT-III subunits, IST1 (aka CHMP8) and CHMP1B, can coassemble as an external protein coat around liposomes in vitro and around recycling endosomal tubules in living cells. Here we show that recombinant IST1 and CHMP1B can also copolymerize into double stranded filaments that surround nucleic acids. Electron cryo-microscopy reconstructions of nucleic acid-bound IST1-CHMP1B copolymers revealed that the polynucleotides track along a binding groove formed between filaments of the inner CHMP1B strand. The well-ordered structures also reveal that the C-terminal tails of CHMP1B subunits extrude through the outer IST1 layer to the tube exterior. As a result, the MIT domain binding motifs of both CHMP1B and IST1 are arrayed on the outer surface of the copolymer, where they could bind and recruit MIT domain-containing co-factors, such as the SPASTIN ATPase or the USP8 ubiquitin protease. Our structure raises the possibility that ESCRT-III proteins may form nucleic acid complexes in mammalian cells.

biochemistry↗