Year: 2026
Type: preprint
Abstract: Marfan syndrome (MFS) causes thoracic aortic aneurysm through mutations in the fibrillin-1 gene and subsequent dysregulated TGF-β signalling. Mixed lineage kinase domain-like protein (MLKL) executes necroptosis after RIPK3-dependent phosphorylation, but also functions in endosomal trafficking. Here we show that MLKL phosphorylation sustains TGF-β receptor recycling and aortic wall integrity without causing cell death. Phosphorylation-dead MLKL S345A/S347A ( Mlkl AA ) mice developed aortic root dilation with disorganised collagen architecture and a secretory-pathway proteomic signature. Crossing them with Fbn1 C1039G /+ MFS mice aggravated aortic dilation, disrupted collagen fibril ultrastructure and prolyl/lysyl hydroxylation, and caused lethal rupture under angiotensin II. Complete MLKL deficiency reproduced this phenotype. Phosphorylated MLKL was increased in MFS aortas, yet cleaved caspase-3, TUNEL positivity, smooth muscle cell content and leukocyte infiltration were unchanged. In smooth muscle cells, MLKL depletion dysregulated collagen-modifying enzymes, altered TGF-β-driven matrix remodelling and impaired RAB11-dependent TGFβR1 recycling. These findings suggest that phosphorylation-dependent, non-lytic functions of MLKL may contribute to the maintenance of thoracic aortic integrity in MFS.
Authors: Harshal Nemade, Henning Guthoff, Oscar Zimmermann, Sophia Riemen, Helena Stiller, Manuel Hedbawny, Bill Agbowo, Daniel Zahnow, Falk Holtkamp, Per Arkenberg, Dennis Mehrkens, Philipp Jahn, Felix Sebastian Nettersheim, Patrik Schelemei, Felix Ruben Picard, Kristel Martínez Lagunas, Jayashree Jayachandran, Gerhard Sengle, Uris Ros, Holger Winkels, Thomas Riffelmacher, Stephan Baldus, Ana J García-Sáez, Matti Adam, Martin Mollenhauer
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W7221720471