https://mednexus.org/doi/10.1097/JBR.0000000000000039
Zinc-finger protein A20 protects hair cells from damage made by high-power microwave
Published Online: 17 September 2019
Inner
ear hair cells are important for maintaining hearing. Irreversible
damage to hair cells is an important cause of sensorineural deafness.
Electromagnetic radiation, especially high-power microwave, is an
important threat to human health in modern society and war. However, it
is not clear whether high-power microwave has an effect on cochlea hair
cells. This study aimed to assess the effects of high-power microwave on
cochlear hair cells in guinea pigs, and investigate the potential
protection of these cells against high-power microwave-induced damage by
recombinant adenovirus A20. Based on experimental results, a 65 W/cm2
irradiation density applied to guinea pigs in this study to establish a
high-power microwave inner ear injury model. In addition, pAdEeay-1/A20
was injected via a round window into experimental guinea pig cochlea,
whereas artificial perilymph was injected into the control group.
Auditory function was assessed by testing the auditory brainstem
response threshold, and damage to cochlear hair cells was investigated
by cell counting and scanning electron microscopy observations of the
basilar membrane. Inner ear injury was observed 6 hours after 65 W/cm2 of irradiation and the auditory brainstem response threshold was significantly higher in the irradiation group (P
< 0.05) compared with other groups. Propidium iodide staining and
scanning electron microscopy results indicated that significant
morphological changes occurred after radiation, especially to inner hair
cells, which exhibited remarkable damage and the presence of several
unknown spherical substances. Auditory brainstem response threshold was
decreased in the pAdEeay-1/A20 group compared with the artificial
perilymph group; moreover, damage to hair cells was milder in the
pAdEeay-1/A20 group compared with the control group (P <
0.01). Thus, high-power microwave can cause damage to cochlear hair
cells, as well as hearing loss with prolonged exposure and/or high
dosage. In this regard, 65 W/cm2 of irradiation for 6 hours
is a reliable target dose for observation of damage. The zinc finger
protein A20 can protect cochlear hair cells from high-power
microwave-induced damage and prevent further hearing loss. This study
was approved by the Laboratory Animal Welfare and Ethics Committee of
the Third Military Medical University, China on April 18, 2017.
Introduction
With
the advance of industrial applications of radiation
in modern society,
humans are increasingly subjected to electromagnetic radiation.[
1]
In modern warfare, electromagnetic radiation, especially
high-power
microwave (HPM), poses a growing threat to human health. However,
whether and how electromagnetic radiation can affect cochlear hair cells
remains unclear. HPM refers to electromagnetic waves with peak power
exceeding 100 MW and frequencies ranging from 1 to 300 GHz, thus
spanning centimeter and millimeter bands. The biological effects of HPM
represent a new, hot research topic that has accompanied the development
of HPM weapons. Indeed, the advent of HPM has greatly attracted
attention to its biological effects, as resulting injuries are not only
caused by direct exposure to microwave weaponry, but also by frequent
low-dose HPM exposure and accidental high-dose HPM leaks occurring
during
microwave weapon production and training. Importantly, HPM
contains some unique effects that are not readily observed with ordinary
biological waves. To date, several studies have focused on the
biological effects of microwaves on vital organs; however, no previous
research examined the effects of HPM on the auditory system. Hence, it
is essential to study the mechanisms by which HPM causes damage to
cochlear hair cells.
AbstractHPM-induced
damage to organisms has attracted significant attention form scholars.
Indeed, previous studies have shown that HPM has harmful effects on
several human organs and systems.[
2,
3] In particular, t
he nervous,[4] cardiovascular,[5] immune, and reproductive[6,7]
systems are target organs that may be negatively affected by HPM, with
adverse consequences such as nerve weakness, memory loss, myocardial
injury, hematopoietic dysfunction, and declined sperm motility. The
influence of microwave on auditory morphology has been gradually
studied. Initially, Yu et al[
8,
9]
found that a high-power electromagnetic pulse could lead to increased
auditory brainstem response (ABR) thresholds in mice. Subsequently, Feng
et al[
10] reported that prolonged exposure to microwaves could lead to
dysfunction of outer hair cells. Later, Seckin et al[
11]
demonstrated that
radiofrequency radiation caused damage to cell
structures of the cochlea during rat development. However, studies
examining pathological changes elicited by HPM in cochlear hair cells
and potential protective effects are still lacking. Hence, in this
study, we established an HPM-induced hair cell injury model to observe
the effects of HPM on guinea pig cochlear hair cells.
The
zinc finger protein A20 was initially discovered in 1990 in human
endothelial cells as a response product to tumor necrosis factor.[
12]
Through gene sequencing, it was found that its readable frame encoded a
new zinc finger protein, named
zinc finger protein A20 or just A20 for
brevity.
It has been revealed that A20 can inhibit nuclear factor-kappa B
(NF-κB) and caspase-3 expression to protect cells form damage,[13,14] such as apoptosis of endothelial cells[15] and nerve cells.[16]
Auditory hair cells are the primary sensory receptors of the mammalian
cochlea, irreversible damage to hair cells is an important cause of
sensorineural deafness. Previous research has shown that hair cell
damage is mainly caused by
caspase-3 activation,
release of reactive
oxygen species, and
NF-κB activation.[
17,
18]
This is consistent with the anti-damage mechanism of A20, so we chose
the zinc finger protein A20 for this initial examination of a protective
effect in HPM-induced hair cell injury model. We constructed a
recombinant adenovirus pAdEeay-1/A20 containing
the zinc finger protein
A20 gene to investigate potential protection of hair cells from
HPM-induced damage. Adenovirus is an effective vector for gene therapy
of inner ear, and does not cause damage to inner ear function.[
19]
With regard to the importance of hearing both during peacetime and
wartime, it is of great theoretical value and practical significance to
study the effect of electromagnetic radiation on hearing function.
( Kommentti tässä välissä)
: Genecaards : HAKU "A20" VASTAUIS: TNFAIP3
A20, Cr. 6q23.3 , Gene:, Zincfinger protein A20
Recommended name: Tumor necrosis factor alpha-induced protein 3
KOMMENTTEJANI: (Tuumorinekroosifaktori alfan aiheuttama proteiini 3. Proteiinin luonnetta ja ryhmää kuvaavia nimiä: OTUD7C, epätavallinen ubikitinaasi-deubikitinaasi proteiini, Omaa C-terminaalissa 7 sinkkisormea josta nimi: Zinc finger protein A20.
GeneCards Symbol:
TNFAIP3
2
TNF Alpha Induced Protein 3
2
3
5
OTUD7C
2
3
4
5
A20
2
3
5
Tumor Necrosis Factor Alpha-Induced Protein 3
3
4
OTU Domain-Containing Protein 7C
3
4
Putative DNA-Binding Protein A20
3
4
Zinc Finger Protein A20
3
4
Tumor Necrosis Factor, Alpha-Induced Protein 3 Tumor Necrosis Factor, Alpha Induced Protein 3 3
-
This gene was identified as a gene whose
expression is rapidly induced by the tumor necrosis factor (TNF). The
protein encoded by this gene is a zinc finger protein and
ubiqitin-editing enzyme, and has been shown to inhibit NF-kappa B
activation as well as TNF-mediated apoptosis. The encoded protein, which
has both ubiquitin ligase and deubiquitinase activities, is involved in
the cytokine-mediated immune and inflammatory responses. Several
transcript variants encoding the same protein have been found for this
gene. [provided by RefSeq, Jul 2012]
Ubiquitin-editing enzyme that contains both ubiquitin ligase and
deubiquitinase activities. Involved in immune and inflammatory responses
signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens
via Toll-like receptors (TLRs) through terminating NF-kappa-B activity.
Tässä artikkelissa annetaan nimeltä tärkeitä ubikitiinia editoivien kompleksin välttämättömien jäsenten nimiä: kuten RNF11 ( RING finger proteiini11) , ITCH
Essential component of a ubiquitin-editing protein complex, comprising
also RNF11, ITCH and TAX1BP1, that ensures the transient nature of
inflammatory signaling pathways. In cooperation with TAX1BP1 promotes
disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and
TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and
BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In
cooperation with TAX1BP1 promotes ubiquitination of UBE2N and
proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation,
deubiquitinates 'Lys-63'-polyubiquitin chains on RIPK1 and catalyzes the
formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1
proteasomal degradation and consequently termination of the TNF- or
LPS-mediated activation of NF-kappa-B. Deubiquitinates TRAF6 probably
acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor
(TCR)-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin
chains on MALT1 thereby mediating disassociation of the CBM
(CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK
activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by
TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation
by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also
inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which
involves polyubiquitin; polyubiquitin promotes association with IKBKG
and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for
lysosomal degradation. In vitro able to deubiquitinate 'Lys-11'-,
'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed
cell death. Has a role in the function of the lymphoid system. Required
for LPS-induced production of pro-inflammatory cytokines and IFN beta in
LPS-tolerized macrophages.
(
TNAP3_HUMAN,P21580 )
Protein attributes for TNFAIP3 Gene
- Size:
- 790 amino acids
- Molecular mass:
- 89614 Da
- Protein existence level:
- PE1
- Quaternary structure:
- Homodimer.
Interacts with TNIP1, TAX1BP1 and TRAF2.
Interacts
with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these
interaction are transient and they are lost after 1 hour of stimulation
with TNF (By similarity).
Interacts with YWHAZ and YWHAH.
Interacts with IKBKG; the interaction is induced by TNF stimulation and by polyubiquitin.
Interacts with RIPK1.
Interacts with UBE2N; the interaction requires TAX1BP1.
Interacts with TRAF6; the interaction is inhibited by HTLV-1 protein Tax.
Gene Families for TNFAIP3 Gene
- HGNC:
-
- The Human Protein Atlas (HPA):
-
- Cancer-related genes
- Disease related genes
- Enzymes
- Human disease related genes
- Plasma proteins
- Potential drug targets
- Predicted intracellular proteins
Protein Domains for TNFAIP3 Gene
-
- Blocks:
-
-
OTU-like cysteine protease
-
Zn-finger, A20-like
( Taulukossa kaikki OTU geenit, jotka ovat
deubikitinaaseja ("DUB") mutta tämä A20 omaa sekä UB ett DUB funktiota.
A20 on " unclassified E3", " Both Ligase AND DUB" , OTUD7C.
(https://www.genenames.org/data/genegroup/#!/group/669 ). (Minulla on kaikki OTUS geenit vihkossa DUB, deubikitinaasit, Ovarian tumor proteases 1 seulontaa. ).
(1)
RNF11 on Essential component of a ubiquitin-editing protein complex, comprising
also TNFAIP3 (Alias A20), ITCH (HECT ryhmän E3 ub. ligaasi) and TAX1BP1, that ensures the transient nature of
inflammatory signaling pathways. (Kommentti: Tässä katsoin tarkemmin molekyyliä Tax1bp1 JA LÖYSIN SIITÄ DOMAANIN JOSSA ON SINKKISORMI.FUNKTIO: (ubz, UBIKITIINIÅ SITOVA SINKKISORMI, calcoco½).
JATKUU..
Promotes the association of TNFAIP3 to
RIPK1 after TNF stimulation. TNFAIP3 deubiquitinates 'Lys-63'
polyubiquitin chains on RIPK1 and catalyzes the formation of
'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal
degradation and consequently termination of the TNF- or LPS-mediated
activation of NF-kappa-B. Recruits STAMBP to the E3 ubiquitin-ligase
SMURF2 for ubiquitination, leading to its degradation by the 26S
proteasome.
(
RNF11_HUMAN,Q9Y3C5 )
Protein Domains for RNF11 Gene
(2)
(Lisätieto ITCH GEENISTÄ JA PROTEIINISTA. Se tekee runsaasti interaktioita ja iso liuta viruksia mainitaan sen interaktioitten yhteydessä. ITCH mainitaan essentielliksi siinä ubikitiinia editoivassa kompleksissa, jossa toimii A20.
ITCH kuuluu ubikitiinia editoivien entsyymien HECT ryhmään ja siinä on 4 WW tunnuksena. . Komleksien täysi monipuolinen jäsenmäärä vastaa tapahtumien hetkellisyyksistä ja ohimenevyyksistä, "transient nature", mikä on plastista biologista elämää kehossa. Esim kuten hyvin toimiva yhteiskunta, jossa roskat heti poistetaan näkyvistä ja hyödynnetään, jolloin on joustavuutta ja valmiutta ja viihtyvyyttä). Kun on tullut merkki tulehduksesta TNF, myös tämä ItCH (
Recommended name: E3 ubiquitin-protein ligase Itchy homolog #Involved in the control of inflammatory signaling pathways (PubMed:
19131965).
Essential component of a ubiquitin-editing protein complex, comprising
also
TNFAIP3 (A20), TAX1BP1 and
RNF11, that ensures
the transient nature of
inflammatory signaling pathways (PubMed:
19131965). Promotes the association of the complex
after TNF stimulation (PubMed:
19131965).
Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63'
polyubiquitin chains on RIPK1 and catalyzes the formation of
'Lys-48'-polyubiquitin chains (PubMed:
19131965).
This leads to RIPK1 proteasomal degradation and consequently
termination of the TNF- or LPS-mediated activation of NFKB1" (PubMed:
19131965).
Gene Families for ITCH Gene
- HGNC:
-
- The Human Protein Atlas (HPA):
-
- Disease related genes
- Enzymes
- Human disease related genes
- Metabolic proteins
- Potential drug targets
- Predicted intracellular proteins
Protein Domains for ITCH Gene
- InterPro:
-
- Blocks:
-
-
C2 domain
-
WW domain signature
-
HECT domain (Ubiquitin-protein ligase)
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