Multitasking Kinase RIPK1 Regulates Cell Death and Inflammation

Newton, Kim

doi:10.1101/cshperspect.a036368

Cited by 71 publications

(53 citation statements)

References 205 publications

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“…PGRN abundance is modulated in response to RIPK1-mediated phosphorylation [118], whose activation can sense viral or toxic nucleotides via the toll-like receptor TLR3 [93, 129], drives pro-inflammatory necroptosis [234], and is implicated in ALS [81, 230]. Consistent with these reports, enhanced RIPK1 protein levels were observed in the spinal cord of Atxn2 -CAG100-KIN mice, possibly with a 1.4-fold abundance already at 3 months, but achieving significance only for the 1.5-fold increase at the age of 14 months (Figure 3C/D).…”

Section: Resultsmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology.Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies. Introduction:Within the dynamic research field into neurodegenerative disorders, the rare monogenic variant SCA2 (Spinocerebellar Ataxia type 2) gained much attention over the past decade, since its pathogenesis is intertwined with the motor neuron diseases ALS/FTLD (Amyotrophic Lateral Sclerosis / Fronto-Temporal Lobar Dementia) and with extrapyramidal syndromes such as Parkinson/PSP (Progressive Supranuclear Palsy). Particularly in the past year, it received massive interest since antisense-oligonucleotides were shown to effectively prevent the disease in mouse models, with clinical trials now being imminent. Still, there is an urgent unmet need to define the molecular events of pathogenesis and to identify biomarkers of progression in SCA2 patients, which reflect therapeutic benefits much more rapidly than clinical rating scales, brain imaging volumetry or neurophysiology measures.SCA2 was first described as separate entity in Indian patients, based on the characteristic early slowing of eye saccadic movements [222]. A molecularly homogeneous founder population of ~1,000 patients in...

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Section: Resultsmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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“…These developments have sparked a large number of studies addressing the mechanisms regulating the different types of regulated cell death and their role in physiology and disease, which have been covered in a number of comprehensive reviews during the last years [3,5,[8][9][10]. The aim of the present short article is not to comprehensively cover the large literature on cell death, but rather to discuss most recent studies that shed light on new mechanisms regulating and connecting necroptosis and pyroptosis, focusing particularly on the role of caspase-8 and RIPK1 as essential players in a complex network of cell death signalling.…”

Section: Introductionmentioning

confidence: 99%

New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8

Schwarzer

Laurien

Pasparakis

2020

Current Opinion in Cell Biology

123

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Necroptosis and pyroptosis are inflammatory forms of regulated necrotic cell death as opposed to apoptosis that is generally considered immunologically silent. Recent studies revealed unexpected links in the pathways regulating and executing cell death in response to activation of signalling cascades inducing apoptosis, necroptosis and pyroptosis. Emerging evidence suggests that RIPK1 and caspase-8 control the crosstalk between apoptosis, necroptosis and pyroptosis and determine the type of cell death induced in response to activation of cell death signalling.

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“…Studies in RIPK1deficient mice and cells showed that RIPK1 acts as a scaffold independently of its kinase activity to regulate pro-inflammatory and pro-survival TNFR1 and TLR3/4 signaling, a function that is essential for mouse development and tissue homeostasis [3][4][5][6][7][8][9][10] . In contrast, RIPK1 kinase activity induces cell death by activating either caspase-8-dependent apoptosis or RIPK3-mixed lineage kinase like (MLKL)-dependent necroptosis 1,2,11,12 . Multiple studies using genetic or pharmacological inhibition have identified RIPK1 kinase activity-dependent cell death as a potent trigger of inflammation in different tissues [13][14][15][16][17] .…”

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confidence: 99%

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation

et al. 2020

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Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.

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Multitasking Kinase RIPK1 Regulates Cell Death and Inflammation

Cited by 71 publications

References 205 publications

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation

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