Редактирование: MLKL (раздел)

==Publications==

{{medline-entry
|title=Casein kinase 1G2 suppresses necroptosis-promoted testis aging by inhibiting receptor-interacting kinase 3.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33206046
|abstract=Casein kinases are a large family of intracellular serine/threonine kinases that control a variety of cellular signaling functions. Here we report that a member of casein kinase 1 family, casein kinase 1G2, [[CSNK1G2]], binds and inhibits the activation of receptor-interacting kinase 3, [[RIPK3]], thereby attenuating [[RIPK3]]-mediated necroptosis. The binding of [[CSNK1G2]] to [[RIPK3]] is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. [[CSNK1G2]]-knockout mice showed significantly enhanced necroptosis response and premature aging of their testis, a phenotype that was rescued by either double knockout of the [i]Ripk3[/i] gene or feeding the animal with a [[RIPK1]] kinase inhibitor-containing diet. Moreover, [[CSNK1G2]] is also co-expressed with [[RIPK3]] in human testis, and the necroptosis activation marker phospho-[[MLKL]] was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the [[RIPK3]]-mediated and [[CSNK1G2]]-attenuated necroptosis is evolutionarily conserved between mice and men.

|keywords=* aging
* cell biology
* mouse
* necroptosis
* protein kinase
* reproductivity
* testis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673785
}}
{{medline-entry
|title=Remifentanil preconditioning protects against hypoxia-induced senescence and necroptosis in human cardiac myocytes [i]in vitro[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32584786
|abstract=Remifentanil and other opioids are suggested to be protective against ischemia-reperfusion injury in animal models and coronary artery bypass surgery patients, however the molecular basis of such protection is far from being understood. In the present study, we have used a model of human cardiomyocytes treated with the hypoxia-mimetic agent cobalt chloride to investigate remifentanil preconditioning-based adaptive responses and underlying mechanisms. Hypoxic conditions promoted oxidative and nitrosative stress, p21-mediated cellular senescence and the activation of necroptotic pathway that was accompanied by a 2.2-, 9.6- and 8.2-fold increase in phosphorylation status of mixed lineage kinase domain-like pseudokinase ([[MLKL]]) and release of pro-inflammatory cytokine IL-8 and cardiac troponin I, a marker of myocardial damage, respectively. Remifentanil preconditioning was able to lower hypoxia-mediated protein carbonylation and limit [[MLKL]]-based signaling and pro-inflammatory response to almost normoxic control levels, and decrease hypoxia-induced pro-senescent activity of about 21% compared to control hypoxic conditions. In summary, we have shown for the first time that remifentanil can protect human cardiomyocytes against hypoxia-induced cellular senescence and necroptosis that may have importance with respect to the use of remifentanil to diminish myocardial ischemia and reperfusion injury in patients undergoing cardiac surgery.

|keywords=* cardiomyocytes
* hypoxia
* necroptosis
* remifentanil
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425462
}}
{{medline-entry
|title=Crucial role of the terminal complement complex in chondrocyte death and hypertrophy after cartilage trauma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31981738
|abstract=Innate immune response and particularly terminal complement complex (TCC) deposition are thought to be involved in the pathogenesis of posttraumatic osteoarthritis. However, the possible role of TCC in regulated cell death as well as chondrocyte hypertrophy and senescence has not been unraveled so far and was first addressed using an ex vivo human cartilage trauma-model. Cartilage explants were subjected to blunt impact (0.59 J) and exposed to human serum (HS) and cartilage homogenate (HG) with or without different potential therapeutics: [[RIPK1]]-inhibitor Necrostatin-1 (Nec), caspase-inhibitor zVAD, antioxidant N-acetyl cysteine (NAC) and TCC-inhibitors aurintricarboxylic acid (ATA) and clusterin (CLU). Cell death and hypertrophy/senescence-associated markers were evaluated on mRNA and protein level. Addition of HS resulted in significantly enhanced TCC deposition on chondrocytes and decrease of cell viability after trauma. This effect was potentiated by HG and was associated with expression of [[RIPK3]], [[MLKL]] and [[CASP8]]. Cytotoxicity of HS could be prevented by heat-inactivation or specific inhibitors, whereby combination of Nec and zVAD as well as ATA exhibited highest cell protection. Moreover, HS HG exposition enhanced the gene expression of [[CXCL1]], IL-8, [[RUNX2]] and [[VEGFA]] as well as secretion of IL-6 after cartilage trauma. Our findings imply crucial involvement of the complement system and primarily TCC in regulated cell death and phenotypic changes of chondrocytes after cartilage trauma. Inhibition of TCC formation or downstream signaling largely modified serum-induced pathophysiologic effects and might therefore represent a therapeutic target to maintain the survival and chondrogenic character of cartilage cells.

|keywords=* Aurintricarboxylic acid
* Cartilage trauma
* Hypertrophy
* Regulated cell death
* Senescence
* Terminal complement complex
|full-text-url=https://sci-hub.do/10.1016/j.joca.2020.01.004
}}
{{medline-entry
|title=Necroptosis increases with age and is reduced by dietary restriction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29696779
|abstract=Necroptosis is a newly identified programmed cell death pathway that is highly proinflammatory due to the release of cellular components that promote inflammation. To determine whether necroptosis might play a role in inflammaging, we studied the effect of age and dietary restriction (DR) on necroptosis in the epididymal white adipose tissue (eWAT), a major source of proinflammatory cytokines. Phosphorylated [[MLKL]] and [[RIPK3]], markers of necroptosis, were increased 2.7- and 1.9-fold, respectively, in eWAT of old mice compared to adult mice, and DR reduced P-[[MLKL]] and P-[[RIPK3]] to levels similar to adult mice. An increase in the expression of [[RIPK1]] (1.6-fold) and [[MLKL]] (2.7-fold), not [[RIPK3]], was also observed in eWAT of old mice, which was reduced by DR in old mice. The increase in necroptosis was paralleled by an increase in 14 inflammatory cytokines, including the pro-inflammatory cytokines IL-6 (3.9-fold), [[TNF]]-α (4.7-fold), and IL-1β (5.1-fold)], and 11 chemokines in old mice. DR attenuated the expression of IL-6, [[TNF]]-α, and IL-1β as well as 85% of the other cytokines/chemokines induced with age. In contrast, inguinal WAT (iWAT), which is less inflammatory, did not show any significant increase with age in the levels of P-[[MLKL]] and [[MLKL]] or inflammatory cytokines/chemokines. Because the changes in biomarkers of necroptosis in eWAT with age and DR paralleled the changes in the expression of pro-inflammatory cytokines, our data support the possibility that necroptosis might play a role in increased chronic inflammation observed with age.
|mesh-terms=* Age Factors
* Animals
* Apoptosis
* Caloric Restriction
* Inflammation
* Mice
* Necrosis
|keywords=* adipose tissue
* aging
* dietary restriction
* inflammaging
* inflammation
* necroptosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052392
}}
{{medline-entry
|title=[[RIPK1]]-[[RIPK3]]-[[MLKL]]-dependent necrosis promotes the aging of mouse male reproductive system.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28807105
|abstract=A pair of kinases, [[RIPK1]] and [[RIPK3]], as well as the [[RIPK3]] substrate [[MLKL]] cause a form of programmed necrotic cell death in mammals termed necroptosis. We report here that male reproductive organs of both [i]Ripk[/i]3- and [i]Mlkl[/i]-knockout mice retain 'youthful' morphology and function into advanced age, while those of age-matched wild-type mice deteriorate. The [[RIPK3]] phosphorylation of [[MLKL]], the activation marker of necroptosis, is detected in spermatogonial stem cells in the testes of old but not in young wild-type mice. When the testes of young wild-type mice are given a local necroptotic stimulus, their reproductive organs showed accelerated aging. Feeding of wild-type mice with an [[RIPK1]] inhibitor prior to the normal onset of age-related changes in their reproductive organs blocked the appearance of signs of aging. Thus, necroptosis in testes promotes the aging-associated deterioration of the male reproductive system in mice.
|mesh-terms=* Aging
* Animals
* Genitalia, Male
* Male
* Mice, Knockout
* Necrosis
* Protein Kinases
* Receptor-Interacting Protein Serine-Threonine Kinases
|keywords=* aging
* apoptosis
* cell biology
* mouse
* necroptosis
* spermatogonia
* testis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557593
}}