Fokusoin kompleksiin joka seuraavassa toimii (edellisestä artikkelista sitaatti) : anti-damage mechanism of A20
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
A20 , anti-damage mechanism ( OTUD7C Alias znf protein A20)
https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNFAIP3&keywords=ZNF,A20
TNFIP3, Tumor Necrosis Factor Alpha-Induced Protein 3 3 4
OTUD7C, OTU Domain-Containing Protein 7C 3 4
Putative DNA-Binding Protein A20 3 4
Zinc Finger Protein A20 3 4
Tulehdus ja vauriotekijöitä: TNF3alfa, NF-kB, caspase-3 , ROS , damage factor side
https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00365/fullStructure of TNF and TNF Receptors
TNF is a type II transmembrane protein that is expressed at the plasma membrane as a trimer (Vassalli, 1992). Cleavage by tumor necrosis factor converting enzyme (TACE) can generate a soluble ligand that propagates signaling by binding to two receptors – TNFR1 (CD120a) and TNFR2 (CD120b) (Black et al., 1997; Moss et al., 1997). TNFR1 associates strongly with both membrane-bound and soluble TNF, while TNFR2 has much higher binding affinity for membrane-bound TNF (Grell et al., 1995). The extracellular region of both receptors has four homologous cysteine-rich domains (CRDs) but their intracellular regions are structurally different. The intracellular portion of TNFR1 possesses a protein-binding region called a death domain (DD), which allows homo- and hetero-typic interactions with other DD-containing proteins. TNFR2, on the other hand, has a TNF Receptor Associated Factor (TRAF) binding site that interacts with the TRAF family of signaling adaptors (Grell et al., 1995; Reddy et al., 2000). The distinct expression profiles and stark difference in the intracellular regions of the TNF receptors greatly influence their physiological roles and cellular activity. Through engaging DD adaptors, broadly expressed TNFR1 can activate proliferative nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling as well as cell death (Wallach et al., 1999; Sessler et al., 2013). On the other hand, TNFR2 is mostly expressed in immune and endothelial tissues. In addition, since it lacks a DD, TNFR2 cannot stimulate cell death, but uses TRAF recruitment to trigger NF-κB and MAPK activation (Wallach et al., 1999; Sessler et al., 2013). Due to its wide spectrum of cellular activities and ubiquitous expression, TNFR1 plays a prevailing role in TNF signaling and will be more extensively covered in this article.
Katso kuva 1. Siinä näkyy A20 asema estämässä aktivoitumistietä tässä setissä. Tämä ei ole se kompleksi joka toimii korvan kuulosolun suojana. Komplekseja on monenlaisia eri tilanteissa.
Activation of NF-κB and Mapk Signaling by TNF
Binding of TNF to TNFR1 triggers receptor trimerization and leads to the assembly of the TNFR1-associated signaling complex (complex I) (Figure 1). Within complex I, the adaptor proteins receptor interacting protein 1 (RIP1; RIPK1) and TNF receptor associated death domain (TRADD) are recruited to TNFR1 through their respective death domains (Micheau and Tschopp, 2003). TRADD then recruits adaptor proteins TRAF2 and TRAF5, which enables the engagement of the E3 ligases cellular inhibitors of apoptosis 1 and 2 (c-IAP1, c-IAP2) and subsequent ubiquitination of various components of complex I (Bertrand et al., 2008; Mahoney et al., 2008; Varfolomeev et al., 2008; Dynek et al., 2010). c-IAP1/2 promote self-ubiquitination and ubiquitination of RIP1 with K63-, K48-, and K11-linked chains, which are critical for TNFR1 complex I signaling
https://www.nature.com/articles/s41419-019-1937-y/figures/7 KUVA. solukko on suolen endoteeliä.
jatkuu
Vihkoon kuvia TNF signaloinnista, jossa A20 indisoituu. Se ilmenee minuuteissa TNF:lle ollen konstitutiivinen ja suojaa soluja TNF:n aikaansaamaa apoptoosia vastaan.
https://mednexus.org/doi/10.1097/JBR.0000000000000039
EMR vaurio mekanimeista https://encyclopedia.pub/entry/26671
MYÖS KEAP1/NRF2 akselin pitää toimia, jota kuuleminen onnistuu.
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