A cell death-independent role for MLKL in TGF-β receptor recycling in Marfan syndrome
- 1Department III of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Abstract
Marfan syndrome (MFS) causes thoracic aortic aneurysm through mutations in the fibrillin-1 gene and subsequent dysregulated TGF-{beta} 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-{beta} receptor recycling and aortic wall integrity without causing cell death. Phosphorylation-dead MLKLS345A/S347A (MlklAA) mice developed aortic root dilation with disorganised collagen architecture and a secretory-pathway proteomic signature. Crossing them with Fbn1C1039G/+ 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-{beta}-driven matrix remodelling and impaired RAB11-dependent TGF{beta}R1 recycling. These findings suggest that phosphorylation-dependent, non-lytic functions of MLKL may contribute to the maintenance of thoracic aortic integrity in MFS.
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BibTeX
@misc{nemade2026cell,
title = {{A cell death-independent role for MLKL in TGF-β receptor recycling in Marfan syndrome}},
author = {H. Nemade and H. Guthoff and O. Zimmermann and S. Riemen and H. Stiller and M. Hedbawny and B. Agbowo and D. Zahnow and F. Holtkamp and P. Arkenberg and D. Mehrkens and P. Jahn and F. S. Nettersheim and P. Schelemei and F. R. Picard and K. M. Lagunas and J. Jayachandran and G. Sengle and U. Ros and H. Winkels and T. Riffelmacher and S. Baldus and A. J. Garcia-Saez and M. Adam and M. Mollenhauer},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.757966},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757966v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A cell death-independent role for MLKL in TGF-β receptor recycling in Marfan syndrome
AU - H. Nemade
AU - H. Guthoff
AU - O. Zimmermann
AU - S. Riemen
AU - H. Stiller
AU - M. Hedbawny
AU - B. Agbowo
AU - D. Zahnow
AU - F. Holtkamp
AU - P. Arkenberg
AU - D. Mehrkens
AU - P. Jahn
AU - F. S. Nettersheim
AU - P. Schelemei
AU - F. R. Picard
AU - K. M. Lagunas
AU - J. Jayachandran
AU - G. Sengle
AU - U. Ros
AU - H. Winkels
AU - T. Riffelmacher
AU - S. Baldus
AU - A. J. Garcia-Saez
AU - M. Adam
AU - M. Mollenhauer
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.757966
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.757966v1
AB - Marfan syndrome (MFS) causes thoracic aortic aneurysm through mutations in the fibrillin-1 gene and subsequent dysregulated TGF-{beta} 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-{beta} receptor recycling and aortic wall integrity without causing cell death. Phosphorylation-dead MLKLS345A/S347A (MlklAA) mice developed aortic root dilation with disorganised collagen architecture and a secretory-pathway proteomic signature. Crossing them with Fbn1C1039G/+ 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-{beta}-driven matrix remodelling and impaired RAB11-dependent TGF{beta}R1 recycling. These findings suggest that phosphorylation-dependent, non-lytic functions of MLKL may contribute to the maintenance of thoracic aortic integrity in MFS.
ER -