LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis.
Nieves Peltzer,Maurice Darding,Antonella Montinaro,Peter Draber,Peter Draber,Helena Draberova,Helena Draberova,Sebastian Kupka,Eva Rieser,Amanda Fisher,J. Ciaran Hutchinson,Lucia Taraborrelli,Torsten Hartwig,Elodie Lafont,Tobias L. Haas,Yutaka Shimizu,Charlotta Böiers,Aida Sarr,James A Rickard,James A Rickard,Silvia Alvarez-Diaz,Silvia Alvarez-Diaz,Michael Ashworth,Allison M. Beal,Tariq Enver,John Bertin,William J. Kaiser,Andreas Strasser,Andreas Strasser,John Silke,John Silke,Philippe Bouillet,Philippe Bouillet,Henning Walczak +33 more
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TLDR
The results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death and reveal that when LUBac and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.Abstract:
The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing to deregulation of TNFR1-mediated cell death2-8. In humans, deficiency in the third LUBAC component HOIL-1 causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype9-11. Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, thereby preventing aberrant cell death. Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1-/- (also known as Rbck1-/-) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3-/-Casp8-/-Hoil-1-/- embryos die at late gestation owing to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.read more
Citations
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Breaking the chains: deubiquitylating enzyme specificity begets function.
TL;DR: By opposing protein ubiquitylation, deubiquitylating enzymes (DUBs) regulate various cellular processes, including protein degradation, the DNA damage response, cell signalling and autophagy and have emerged as exciting therapeutic targets within the field of proteostasis.
Journal ArticleDOI
Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease
Najoua Lalaoui,Najoua Lalaoui,Steven E. Boyden,Hirotsugu Oda,Geryl Wood,Deborah L. Stone,Diep Chau,Lin Liu,Lin Liu,Monique Stoffels,Tobias Kratina,Kate E. Lawlor,Kate E. Lawlor,Kristien J. M. Zaal,Patrycja Hoffmann,Nima Etemadi,Nima Etemadi,Kristy Shield-Artin,Kristy Shield-Artin,Christine Biben,Christine Biben,Wanxia Li Tsai,Mary Blake,Hye Sun Kuehn,Dan Yang,Holly Anderton,Holly Anderton,Natasha Silke,Laurens Wachsmuth,Lixin Zheng,Natalia Sampaio Moura,David B. Beck,Gustavo Gutierrez-Cruz,Amanda K. Ombrello,Gineth Pinto-Patarroyo,Andrew J. Kueh,Andrew J. Kueh,Marco J Herold,Marco J Herold,Cathrine Hall,Hongying Wang,Jae Jin Chae,Natalia I. Dmitrieva,Mark D. McKenzie,Mark D. McKenzie,Amanda Light,Beverly K. Barham,Anne Jones,Tina Romeo,Qing Zhou,Ivona Aksentijevich,James C. Mullikin,Andrew J. Gross,Anthony K. Shum,Edwin D. Hawkins,Edwin D. Hawkins,Seth L. Masters,Seth L. Masters,Michael J. Lenardo,Manfred Boehm,Sergio D. Rosenzweig,Manolis Pasparakis,Anne K. Voss,Anne K. Voss,Massimo Gadina,Daniel L. Kastner,John Silke,John Silke +67 more
TL;DR: It is shown that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life, and a cleavage-resistant Ripk1 D325A mutant mouse strain generated limits TNF-induced cell death and inflammation.
Journal ArticleDOI
TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation
Elodie Lafont,Peter Draber,Peter Draber,Eva Rieser,Matthias Reichert,Sebastian Kupka,Diego de Miguel,Helena Draberova,Helena Draberova,Anne von Mässenhausen,Amandeep Bhamra,Stephen Henderson,Katarzyna Wojdyla,Avigayil Chalk,Silvia Surinova,Silvia Surinova,Andreas Linkermann,Henning Walczak +17 more
TL;DR: It is shown that LUBAC activity enables TBK1 and IKKε recruitment to and activation at the TNF receptor 1 signalling complex (TNFR1-SC) and an essential survival function for NEMO is uncovered, whereby it enables the recruitment and activation of these non-canonical IKKs to prevent TNF-induced cell death.
Journal ArticleDOI
ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis).
TL;DR: The master regulators, the innate immune sensor ZBP1 and the essential cell survival kinase TAK1, that play vital roles in the regulation of RIPK1/RIPK3–FADD–caspase-8 cell death complex assembly are reviewed and its versatility in executing Pyroptosis, Apoptosis, and Necroptosis is dubbed here as PAN-optosis.
Journal ArticleDOI
The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis).
TL;DR: Putative components of the PANoptosome are reviewed and a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly are presented to present potential mechanisms governing PANoptosis based on evolutionary analysis.
References
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Journal ArticleDOI
Catalytic activity of the caspase-8–FLIP L complex inhibits RIPK3-dependent necrosis
Andrew Oberst,Christopher P. Dillon,Ricardo Weinlich,Laura L. McCormick,Patrick Fitzgerald,Cristina Pop,Razq Hakem,Guy S. Salvesen,Douglas R. Green +8 more
TL;DR: It is found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIPL, also known as CFLAR), and this complex is required for the protective function.
Journal ArticleDOI
The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal
TL;DR: Sensitivity to TNFalpha-mediated cell death in rip-/- cells is accompanied by a failure to activate the transcription factor NF-kappaB, and the physiologic role(s) that RIP plays in regulating apoptosis in vivo is defined.
Journal ArticleDOI
The Pseudokinase MLKL Mediates Necroptosis via a Molecular Switch Mechanism
James M. Murphy,Peter E. Czabotar,Peter E. Czabotar,Joanne M Hildebrand,Joanne M Hildebrand,Isabelle S Lucet,Jian-Guo Zhang,Jian-Guo Zhang,Silvia Alvarez-Diaz,Silvia Alvarez-Diaz,Rowena S. Lewis,Rowena S. Lewis,Najoua Lalaoui,Najoua Lalaoui,Donald Metcalf,Donald Metcalf,Andrew I. Webb,Andrew I. Webb,Samuel N. Young,Samuel N. Young,Leila N. Varghese,Leila N. Varghese,Gillian M. Tannahill,Gillian M. Tannahill,Esme C. Hatchell,Esme C. Hatchell,Ian J. Majewski,Ian J. Majewski,Toru Okamoto,Toru Okamoto,Renwick C. J. Dobson,Renwick C. J. Dobson,Douglas J. Hilton,Douglas J. Hilton,Jeffrey J. Babon,Jeffrey J. Babon,Nicos A. Nicola,Nicos A. Nicola,Andreas Strasser,Andreas Strasser,John Silke,John Silke,Warren S. Alexander,Warren S. Alexander +43 more
TL;DR: Structural-guided mutation of the MLKL pseudoactive site resulted in constitutive, RIPK3-independent necroptosis, demonstrating that modification ofMLKL is essential for propagation of the ne croptosis pathway downstream of RIPK 3.
Journal ArticleDOI
Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.
Fuminori Tokunaga,Shin-ichi Sakata,Shin-ichi Sakata,Yasushi Saeki,Yoshinori Satomi,Takayoshi Kirisako,Kiyoko Kamei,Kiyoko Kamei,Tomoko Nakagawa,Tomoko Nakagawa,Michiko Kato,Shigeo Murata,Shigeo Murata,Shoji Yamaoka,Masahiro Yamamoto,Shizuo Akira,Toshifumi Takao,Keiji Tanaka,Kazuhiro Iwai,Kazuhiro Iwai +19 more
TL;DR: Results indicate that LUBAC is involved in the physiological regulation of the canonical NF-κB activation pathway through linear polyubiquitylation of NEMO.
Journal ArticleDOI
RIP3 mediates the embryonic lethality of caspase-8-deficient mice
William J. Kaiser,Jason W. Upton,Alyssa B. Long,Devon Livingston-Rosanoff,Lisa P. Daley-Bauer,Razqallah Hakem,Tamara Caspary,Edward S. Mocarski +7 more
TL;DR: It is found that RIP3 is responsible for the mid-gestational death of Casp8-deficient embryos and together completely dispensable for mammalian development.
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