Not Only A Killer A System for Killing!

The next time you're out exercising, spare a thought for your busy mitochondria. NASA scientists just reported mitochondria as the key to health problems in space.

Natural killer (NK) cells can extend membrane probes into cells or pathogens. These are loaded with granulysin (GNLY) to penetrate and perforin (PFN) to kill intracellular bacteria or protozoa and can lyse entire cells. The probes can also transfer healthy mitochondria to apoptotic cardiomyocytes (and other cells) in need of mitochondrial transfer. Uterine NK cells of the decidua send probes into trophoblasts to selectively kill intracellular Listeria monocytogenes without killing the trophoblast host. Stressed cells, moving toward apoptosis can behave similarly, but in reverse shooting out nanoprobes to proximal cells seeking cooperation and urgent mitochondrial transfers including to cancer cells.

A meta-analysis of gene expression signatures for blood pressure and hypertension in 7017 individuals from 6 international studies found of 7717 genes, 34 were most differentialy expressed including GNLY. Enrichment analysis for the diastolic and systolic gene group's associated strongly with NK cell mediated cytotoxicity and 13 other pathways including antigen processing and inflammatory response.

Formation of membrane probes or tubes, in which mitochondria travel and establishment of intracellular mitochondrial networks in the peripheral zone of cells require Kinesin-1 heavy chain (KIF5B). KIF5B is also required for female meiosis (oogenesis) and proper chromosomal segregation in mitotic cells and modulates central spindle organization in late-stage cytokinesis in chondrocytes.

A study of centromere heterochromatin (connected with central spindle) surprisingly showed that distant euchromatic regions, enriched in repressed methylated genes also interacted with the hierarchical organization of centromeric DNA. These 3D spatial interactions (at a distance) are likely mediated by liquid-like fusion events and can influence the health of individuals. Repressed gene's were identified as transposable elements, sequences often associated with pathogenic DNA insertions that have been persistently retained.  

KIF5B is an interaction partner of ADP-ribosylation factor-like 8b (Arl8b), which is required for NK cell–mediated cytotoxicity that drives polarization of lytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between NK and target cells. Silencing experiments that led to failure of MTOC-lytic granule polarization suggest Arl8b and KIF5B together control the critical step in NK cell cytotoxicity. 

KIF5B is also a critical transporter of p53 and c-Myc to the cytoplasm for degradation. However, subcellular localization of Arl8b and p53-dependent cell death was shown to occur through knockdown of acetylation subunit NatC. As a consequence, p53 is stabilized, phosphorylated and significantly activates transcription of downstream proapoptotic genes. In the absence KIF5B, or presence of  mutants p53 and c-Myc aggregate in the nucleus where they signal DNA damage-induced apoptosis through the control of p53 by endogenous c-Myc (in vivo).

Finely tuned, frequently used KIF5B in NK cells expressing GNLY may induce effects on local tissue blood pressure, as was discovered by expression of Renin-Angiotensin vasoactive proteins AT1, AT2, and ANP in pregnancy-induced uterine NK cells. Inflammation signaling, via tissue bound NK cells may result from stretch-mediated release of angiotensin II, which is coupled with p53 acetylation apoptosis and activation of p53. This may prolong upregulation of the local renin-angiotensin system, increase susceptibility of target cells to apoptosis and signal adaptive immune cells. 

Somewhere in the balance between NatC knockdown induced apoptosis and angiotensin II induced apoptosis p53 may direct traffic to keep your cells healthy!

 

p53 in the SARS-CoV2 Storm

Coronavrius induced cytokine storm

A massive simulation and analysis using the supercomputer at Oakridge led scientists to more accurately identify the general idea that a Covid19 induced "cytokine storm" is responsible for disease progression. After detailed genetic analysis they specifically predicted that Bradykinin (BK) initiated the storm. If correct, this would help improve treatment directions for admitted patients. 

BK receptors are coded by BDKRB1 and BDKRB2 (BK2) gene's that operate in a kallikrein-kinin system (KKS), like the Renin Angiotensin System (RAS) as another potent regulator of blood pressure. BK is a part of the vasopressor system that induces hypotension and vasodilation, it is degraded by ACE and enhanced by angiotensin1-9, which is produced by ACE2 the receptor that SARS-COV2 binds. BK has been implicated as being active in the metabolic response to stress.

Similar to angiotensin peptides, BK is produced from an inactive pre-protein kininogen through activation by serine protease kallikrein (KKL). KLK1-KLK15 are mostly represented as a cluster of serine proteases on chromosome 19, with different tissue distributions. 

KLK's 1-15 further evidence a convergence on chromosome 19, associated closely with a large number of genes involved in blood pressure. KLK's are located at 19q13.41, an active transposon region with a 2x background deletion rate clustered near Zinc Fingers and KIR's (Killer cell like receptors). Chr19 is also associated with MHC precursors around which innate immunity and Natural Killer (NK) cell signaling developed. A link was confirmed in mice uterine NK cells that regulated local tissue blood pressure by at least Angiotensin Type 1 Receptor (AT1R) partly in response to mechanical stretch of vasoconstriction and vasodilation induced by uterine NK's internal RAS. 

A study of BK2 confirmed a conserved p53 binding site (rat, mouse and human) and p53-mediated activation of the BK2 promoter was augmented by transcriptional co-activators, CBP/p300. The results demonstrated BK2 promoter as a target of the p53-mediated activation and suggested a new physiological role for p53 in the regulation of G protein-coupled receptor (GPCR) gene expression. 

A follow up study, by the same group explained that Angiotensin II (AngII), the product of Angiotensin-Renin-Angiotensin1-Ace stimulates the phosphorylation of p53 (on serine 15) and CREB (on serine 133), and that AngII signaling converges on the p53-CRE enhancer to stimulate BK2 gene transcription.  

The convergence revealed that AT1R signaling activated CREB phosphorylation and in vivo assembly of p-CREB on the BK2 promoter in conjunction with histone hyperacetylation. It confirmed that AngII stimulates BK2 gene transcription in IMCD3 cells via AT1R. Thus, under conditions of augmented AngII and AT1R signaling, BK expression will be enhanced, thereby maintaining a balance of these two powerful counter-regulatory systems representing a novel form of cross-talk between GPCR's that link RAS and KKS, crucially here via p53.

This combined research indicates that activation of BK2 on endothelial cells, which is mediated by p53 dependent RAS-KKS cross-talk may also implicate AT1R on NK cells to secrete growth disrupting or growth promoting factors in response. SARS-CoV2 bound to ACE2 reduces its availability to convert angiotensin 1 to angiotensin 1-9, which normally enhances BK. The resulting imbalance and increase in circulating angII may directly implicate a NK cells' AT1R RAS response to a CoV2-ACE2 bound cell with disabled p53 promoter of GPCR expression. This cell with a crippled BK2 KKS, hypotension-vasodilation response offers no counter to the the AngII induced NK RAS vasoconstrictive function, affecting local tissue blood pressure thus failing to become a NK target.