LUBAC-mediated M1 Ub regulates necroptosis by segregating the cellular distribution of active MLKL

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Abstract: Plasma membrane accumulation of phosphorylated mixed lineage kinase domain-like (MLKL) is a hallmark of necroptosis, leading to membrane rupture and inflammatory cell death. Pro-death functions of MLKL are tightly controlled by several checkpoints, including phosphorylation. Endo- and exocytosis limit MLKL membrane accumulation and counteract necroptosis, but the exact mechanisms remain poorly understood. Here, we identify linear ubiquitin chain assembly complex (LUBAC)-mediated M1 poly-ubiquitination (poly-Ub) as novel checkpoint for necroptosis regulation downstream of activated MLKL in cells of human origin. Loss of LUBAC activity inhibits tumor necrosis factor α (TNFα)-mediated necroptosis, not by affecting necroptotic signaling, but by preventing membrane accumulation of activated MLKL. Finally, we confirm LUBAC-dependent activation of necroptosis in primary human pancreatic organoids. Our findings identify LUBAC as novel regulator of necroptosis which promotes MLKL membrane accumulation in human cells and pioneer primary human organoids to model necroptosis in near-physiological settings

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: Cell death & disease. - 15, 1 (2024) , 77, ISSN: 2041-4889

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2024

Creator: Weinelt, Nadine
Wächtershäuser, Kaja Nicole
Celik, Gulustan
Jeiler, Birte
Gollin, Isabelle
Zein, Laura
Smith, Sonja
Geoffroy, Andrieux
Das, Tonmoy
Roedig, Jens
Feist, Leonard
Rotter, Björn
Börries, Melanie
Pampaloni, Francesco
Wijk, Sjoerd J. L.

DOI: 10.1038/s41419-024-06447-6

URN: urn:nbn:de:bsz:25-freidok-2440633

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 14.08.2025, 10:56 AM CEST

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Associated

Weinelt, Nadine
Wächtershäuser, Kaja Nicole
Celik, Gulustan
Jeiler, Birte
Gollin, Isabelle
Zein, Laura
Smith, Sonja
Geoffroy, Andrieux
Das, Tonmoy
Roedig, Jens
Feist, Leonard
Rotter, Björn
Börries, Melanie
Pampaloni, Francesco
Wijk, Sjoerd J. L.
Universität

Time of origin

2024

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