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Species-specific LUBAC-mediated M1 ubiquitination counteracts necroptosis by segregating the cellular distribution and fate of activated MLKL
Species-specific LUBAC-mediated M1 ubiquitination counteracts necroptosis by segregating the cellular distribution and fate of activated MLKL
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Length:
20 minutes
Released:
Dec 10, 2022
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Podcast episode
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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.12.08.519265v1?rss=1
Authors: Weinelt, N., Waechtershaeuser, K. N., Smith, S., Andrieux, G., Das, T., Jeiler, B., Roedig, J., Feist, L., Rotter, B., Boerries, M., Pampaloni, F., van Wijk, S. J. L.
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. Endocytosis 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 human cells. Loss of LUBAC activity inhibits necroptosis, without affecting necroptotic signaling, but by preventing membrane accumulation of activated MLKL. Flotillin-1/2 act as putative necroptotic M1 poly-Ub targets that inhibit necroptosis suppression induced by LUBAC inhibition. Finally, we confirm LUBAC-dependent suppression of necroptosis in primary human pancreatic organoids. Our findings identify LUBAC as species-specific regulator of necroptosis which prevents MLKL membrane accumulation and pioneer primary human organoids to model necroptosis in near-physiological settings.
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http://biorxiv.org/cgi/content/short/2022.12.08.519265v1?rss=1
Authors: Weinelt, N., Waechtershaeuser, K. N., Smith, S., Andrieux, G., Das, T., Jeiler, B., Roedig, J., Feist, L., Rotter, B., Boerries, M., Pampaloni, F., van Wijk, S. J. L.
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. Endocytosis 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 human cells. Loss of LUBAC activity inhibits necroptosis, without affecting necroptotic signaling, but by preventing membrane accumulation of activated MLKL. Flotillin-1/2 act as putative necroptotic M1 poly-Ub targets that inhibit necroptosis suppression induced by LUBAC inhibition. Finally, we confirm LUBAC-dependent suppression of necroptosis in primary human pancreatic organoids. Our findings identify LUBAC as species-specific regulator of necroptosis which prevents MLKL membrane accumulation and pioneer primary human organoids to model necroptosis in near-physiological settings.
Copy rights belong to original authors. Visit the link for more info
Podcast created by Paper Player, LLC
Released:
Dec 10, 2022
Format:
Podcast episode
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