Peptidoglikanni tanib olish oqsili - Peptidoglycan recognition protein

Odamning PGLYRP1 oqsilining tuzilishi. Asoslangan PyMOL PDB 1yck-ni ko'rsatish.

Peptidoglikanni tanib olish oqsillari (PGRPlar) yuqori darajada saqlanib qolganlar guruhidir naqshni aniqlash retseptorlari kamida bitta peptidoglikan tanib olish bilan domen ni tanib olishga qodir peptidoglikan ning tarkibiy qismi hujayra devori ning bakteriyalar. Ular mavjud hasharotlar, mollyuskalar, echinodermalar va akkordatlar. PGRPlarning ta'sir qilish mexanizmi taksonlar orasida turlicha. Yilda hasharotlar, PGRPs to'rtta noyob effektor yo'llaridan birini faollashtirish orqali bakteriyalarni bilvosita yo'q qiladi: propenoloksidaza kaskad, pullik yo'l, IMD yo'li va induksiyasi fagotsitoz.[1][2][3][4] Yilda sutemizuvchilar, PGRPlar bakteriyalarni to'g'ridan-to'g'ri hujayra devori yoki tashqi membranasi bilan ta'sir o'tkazish orqali yo'q qiladi yoki peptidoglikanni gidroliz qiladi.[1][2][3][4] Ular shuningdek modulyatsiya qilishadi yallig'lanish va mikrobiom va xost retseptorlari bilan o'zaro ta'sir qiladi.[1][3]

Kashfiyot

Birinchi PGRP 1996 yilda Masaaki Ashida va uning hamkasblari tomonidan topilgan bo'lib, ular tarkibida mavjud bo'lgan 19 kDa oqsilini tozalashgan. gemolimf va kutikula ipak qurti (Bombyx mori ) va "Peptidoglikanni tanib olish oqsili" deb nomladi, chunki u peptidoglikan bilan maxsus bog'langan va propenoloksidaza kaskadini faollashtirgan.[5] 1998 yilda Xekan Shtayner va uning hamkasblari differentsial displey ekranidan foydalanib, kuya ichida PGRP ortologini aniqladilar va klonladilar (Trichoplusia ni ) va keyin kashf qilingan va klonlangan sichqoncha va odamning PGRP ortologlari,[6] Shunday qilib, PGRP hasharotlardan sutemizuvchilarga juda yuqori darajada saqlanib qolganligini ko'rsatadi. Shuningdek, 1998 yilda Sergey Kiselev va uning hamkasblari mustaqil ravishda sichqon adenokarsinomasidan PGRP bilan bir xil ketma-ketlikdagi oqsilni topdilar va klonladilar, ular Tag7 deb nomladilar.[7] 1999 yilda Masanori Ochiai va Masaaki Ashida ipak qurtini klonlashdi (B. mori) PGRP.[8]

2000 yilda mevali pashshaning mavjud ketma-ketligi asosida (Drosophila melanogaster ) genom, Dan Xultmark va uning hamkasblari 12 ta juda xilma-xil PGRP genlaridan iborat oilani topdilar Drosophila,[9] ular o'lchamiga qarab qisqa (S) va uzun (L) shakllarga ajratdilar stenogrammalar. Mavjud ketma-ketliklarni gomologik izlash orqali ular odam va sichqonchaning uzoq shakli PGRP (PGRP-L) mavjudligini bashorat qilishdi.[9]

2001 yilda Roman Dziarski va uning hamkasblari PGRP-L, PGRP-Ia va PGRP-Iβ deb nomlangan uchta odam PGRP-ni topdilar va klonlashdi (uzoq va oraliq o'lchamdagi transkriptlar uchun).[10] Ular 4 ta PGRP oilasi uchun inson genomining kodlarini aniqladilar: PGRP-S (qisqa PGRP)[6] va PGRP-L, PGRP-Ia va PGRP-Iβ.[10] Keyinchalik, Inson Genomlari Tashkiloti Gen nomenklaturasi qo'mitasi PGRP-S, PGRP-L, PGRP-Ia va PGRP-Iβ ning gen belgilarini o'zgartirdi PGLYRP1, PGLYRP2, PGLYRP3va PGLYRP4navbati bilan va ushbu nomenklatura hozirda boshqa sutemizuvchi PGRPlar uchun ham qo'llaniladi. Sergey Kiselev va uning hamkasblari mustaqil ravishda PGLYRP2 (TagL) sichqonchasini klonlashdi.[11][12] Keyinchalik, PGRPlar hayvonot dunyosida aniqlangan, garchi quyi metazoa (masalan, nematod) Caenorhabditis elegans ) va o'simliklarda PGRP yo'q.[2][3][4]

2003 yilda Byung-Xa Oh va uning hamkasblari PGRP-LB ni kristallashtirdilar Drosophila va uning tuzilishini hal qildi.[13]

Turlari

Hasharotlar 19 tagacha hosil qiladi muqobil ravishda qo'shilgan Uzoq (L) va qisqa (S) shakllarga ajratilgan PGRPlar. Masalan, mevali chivin (D. melanogaster) 13 ta PGRP geniga ega, ularning transkriptlari muqobil ravishda 19 ta oqsilga qo'shilgan, chivin esa (Anopheles gambiae ) 7 ta PGRP geniga ega, 9 ta qo'shilish variantlari mavjud.[1][2][9][14]

Insonning joylashishi PGLYRP1 19-xromosomadagi gen va sxematik gen, cDNA va ekzonlar, intronlar va oqsil domenlari ko'rsatilgan oqsil tuzilmalari.
Insonning joylashishi PGLYRP2 19-xromosomadagi gen va sxematik gen, cDNA va ekzonlar, intronlar va oqsil domenlari ko'rsatilgan oqsil tuzilmalari.
Insonning joylashishi PGLYRP3 1-xromosomadagi gen va sxematik gen, cDNA va ekzonlar, intronlar va oqsil domenlari ko'rsatilgan oqsil tuzilmalari.
Insonning joylashishi PGLYRP4 1-xromosomadagi gen va sxematik gen, cDNA va ekzonlar, intronlar va oqsil domenlari ko'rsatilgan oqsil tuzilmalari.

Sutemizuvchilarda to'rttagacha PGRP mavjud bo'lib, ularning hammasi ajralib chiqadi. Bular peptidoglikanni tanib olish oqsili 1 (PGLYRP1), peptidoglikanni tanib olish oqsili 2 (PGLYRP2), peptidoglikanni tanib olish oqsili 3 (PGLYRP3) va peptidoglikanni tanib olish oqsili 4 (PGLYRP4).[1][2][3][4][10]

Tuzilishi

PGRP tarkibida kamida 165 ta aminokislotaning uzunligini tashkil etadigan kamida bitta C-terminalli peptidoglikanni aniqlash sohasi (PGRP domeni) mavjud. Bu peptidoglikan bilan bog'laydigan 2-turdagi amidaza domeni uchun gomologik bakteriyofag va bakterial 2-turdagi amidazalar.[4]

PGRP domenida uchta periferik a-spiral va bir nechta markaziy b-iplar mavjud bo'lib, ular molekulaning old tomonida peptidoglikan bilan bog'laydigan truba hosil qiladi, molekulaning orqa qismida esa ko'pincha gidrofobik, turli xil bo'lgan turli xil PGRP segmenti mavjud. PGRPlar va bakteriofag amidazalarida mavjud emas.[2][3][4][13][15][16]

Omurgasızların PGRP'leri kichik sekretsiya qilingan oqsillar bo'lishi mumkin (masalan, PGRP-SB, -SA, -SD va -LB ichida Drosophila), kattaroq transmembran oqsillari (masalan, PGRP-LA, -LC va -LF in Drosophila) yoki hujayra ichidagi oqsillar (masalan, PGRP-LEfl in Drosophila).[1][2][3][4] Ular odatda bitta C-terminalli PGRP domeniga ega, istisnolardan tashqari Drosophila Ikkita PGRP domeniga ega bo'lgan PGRP-LF.[1] Sutemizuvchilarning PGRPlari odatda dimer hosil qiluvchi va bitta PGRP domenini (masalan, inson PGLYRP1 va PGLYRP2) yoki ikkita PGRP domenini (masalan, inson PGLYRP3 va PGLYRP4) o'z ichiga olgan sekretsiya oqsillari.[1][3][17][18][19]

Vazifalar

Peptidoglikan bilan bog'lanish

PGRPlar bakterial hujayra devorining asosiy tarkibiy qismi bo'lgan peptidoglikanni bog'laydi.[1][2][3][4] Peptidoglikan β (1-4) bilan bog'langan polimerdir N-atsetilglukozamin (GlcNAc) va N-atsetilmuramik kislota (MurNAc) o'zgaruvchan L- va D- dan tashkil topgan qisqa peptidlar bilan o'zaro bog'langanaminokislotalar. MurNAc-tripeptid - bu PGRP-lar bilan bog'lanadigan peptidoglikanning minimal bo'lagi va MurNAc-tetrtapeptidlar va MurNAc-pentapeptidlar yuqori yaqinlik bilan bog'langan.[15][16][20] Peptidoglikan bilan bog'lanish odatda PGRP tuzilishining o'zgarishini yoki majburiy bog'da MurNAc-peptidni qulflaydigan boshqa PGRP molekulasi bilan o'zaro ta'sirni keltirib chiqaradi.[16] Ba'zi PGRPlar peptidoglikanning peptid qismida mavjud bo'lgan turli xil aminokislotalarni, ayniqsa peptidoglikan peptidning uchinchi holatidagi aminokislota o'rtasida farq qilishi mumkin, bu odatda L-lizin yilda Gram-musbat kokklar yoki mezo-diaminopimel kislotasi (m-DAP) in Gram-manfiy bakteriyalar va grammusbat tayoqchalar. Ba'zi PGRPlar MurNAc va uning angidro shaklini ham ajratishi mumkin.[2][15][16][20][21]

Hasharotlarning vazifalari

PGRP-lar hasharotlar tarkibidagi bakteriyalarning asosiy sezgichlari va ularning mikroblarga qarshi mudofaasining asosiy tarkibiy qismidir. PGRP-lar ishlab chiqarishni keltirib chiqaradigan signalli kaskadlarni faollashtiradi mikroblarga qarshi peptidlar va boshqa immun effektorlar. Eriydigan PGRPlar (masalan, PGRP-SA va PGRP-SD in.) Drosophila) tarkibida L-lizin bo'lgan peptidoglikanni aniqlash va endogen ligand hosil qiluvchi proteolitik kaskadni faollashtirish Yomg'ir hujayra sirtidagi Toll-1 retseptorini faollashtiradi. Toll-1 o'z navbatida birinchi navbatda Gram-musbat bakteriyalarga qarshi faol bo'lgan antimikrobiyal peptidlarni ishlab chiqarishga olib keladigan signal o'tkazuvchan kaskadini keltirib chiqaradi. qo'ziqorinlar.[1][2][3][22][23][24][25]

Transmembranli PGRPlar (masalan, Drosophila PGRP-LC) va hujayra ichidagi PGRP (masalan, Drosophila PGRP-LE) retseptorlari sifatida ishlaydi - ular aniqlaydilar m-DAP o'z ichiga olgan peptidoglikan va IMD (immunitet tanqisligi) signalini o'tkazish yo'lini faollashtiradi, bu asosan gram-manfiy bakteriyalarga qarshi faol mikroblarga qarshi peptidlarni ishlab chiqarishni keltirib chiqaradi.[1][2][3][26][27][28] IMD yo'lining bu faollashishi antimikrobiyal hosil qiluvchi ikkilamchi oksidaza hosil bo'lishiga ham sabab bo'ladi reaktiv kislorod turlari.[1][29]

Ba'zi hasharotlar PGRPlari (masalan, Drosophila PGRP-SA va -LE va B. mori PGRP-S) profenoloksidaza kaskadini faollashtiradi, natijada melanin, reaktiv kislorod turlari va boshqa mikroblarga qarshi birikmalar hosil bo'ladi.[3][5][30][31]

Bir nechta kichik hasharotlar PGRP (masalan, Drosophila PGRP-SB, -SC va -LB) bu peptidoglikan gidrolazalar (N-atsetilmuramoyl-L-alanin amidazalar ) MurNAc va L-Ala orasidagi amid bog'lanishini (peptiddagi birinchi aminokislota) gidrolizlaydi.[1][32] Ushbu amidazalar peptidoglikanni tozalash vositasi sifatida ishlaydi, chunki ular hosil bo'lgan peptidoglikan parchalarini PGRP bilan bog'lab bo'lmaydi.[1][32] Ular peptidoglikanning hujayralarni faollashtiradigan qobiliyatini bekor qiladi va bakteriyalar bilan to'ldirilgan ichak traktidan peptidoglikanni tizimli qabul qilishni cheklaydi va mezbon mudofaa yo'llarini pastga regulyatsiya qiladi yoki haddan tashqari faollashishini oldini oladi.[1][33][34] Ushbu amidazalarning ba'zilari to'g'ridan-to'g'ri bakteritsiddir, bu esa xostni infektsiyalardan himoya qiladi va komensal bakteriyalar sonini nazorat qilishga yordam beradi.[35][36]

Boshqa ba'zi hasharotlar PGRPlari (masalan, Drosophila PGRP-LF) peptidoglikanni bog'lamaydi va hujayra ichidagi signalizatsiya domeniga ega emas - ular PGRP-LC bilan murakkablashadi va IMD yo'lining faollashuvini tartibga solish uchun ishlaydi.[1][37][38]

Boshqa umurtqasiz hayvonlarning vazifalari

PGRPlar ko'pgina umurtqasiz hayvonlarda, shu jumladan bakteriyalar tomonidan mavjud bo'lib, ular kontsentratsiyasida ifodalanadi yoki induktsiyalanadi qurtlar,[39] shilliq qurtlar,[40] istiridye,[41][42] taroqlar,[43][44] Kalmar,[45] va dengiz yulduzi.[46] Ushbu PGRPlar tasdiqlangan yoki bashorat qilingan amidazalar, ba'zilari esa antibakterial ta'sirga ega. Ular, ehtimol, xostlarni yuqumli kasalliklardan himoya qiladi yoki ba'zi bir komensal bakteriyalar tomonidan kolonizatsiyani tartibga soladi Vibrio fischeri Gavayi bobtail kalmarining engil organida, Evropima skoloplar.[47][48]

Pastki umurtqali hayvonlardagi ifoda va funktsiyalar

Erta baliqqa o'xshash xordatlar, amfioksi (lanselets ), keng tug'ma immunitet tizimiga ega (ammo adaptiv immunitet yo'q) va bir nechta PGRP genlar - masalan, 18 PGRP Florida lanceletidagi genlar (Branchiostoma floridae ), ularning barchasi peptidoglikan-gidrolizlovchi amidazalar bashorat qilingan va kamida bittasi bakteritsiddir.[49]

Zebrafish kabi baliqlar (Danio rerio ), odatda 4 ga ega PGRP genlar,[50] ammo ularning hammasi ham sutemizuvchilar uchun ortologik emas PGLYRPlar va turli xil turlari bir nechta bo'lishi mumkin PGRP qo'shilish variantlari.[51][52][53][54] Ular kattalar baliqlarining ko'plab to'qimalarida, masalan, jigarda, gilzalar, ichak, oshqozon osti bezi, taloq va teriga va bakteriyalar o'z ifodasini oshirishi mumkin. PGRPlar rivojlanishda ham yuqori darajada ifodalangan oositlar va tuxumlarda (masalan, zebrafish PGLYRP2 va PGLYRP5).[50] Ushbu PGRPlar ikkala peptidoglikan-gidrolizlovchi amidaza faolligiga ega va Gram-musbat va Gram-manfiy bakteriyalarga to'g'ridan-to'g'ri bakteritsid ta'sir ko'rsatadi va tuxumni va rivojlanayotganlarni himoya qiladi. embrionlar bakterial infektsiyalardan.[50] Ular bir nechta signal yo'llarini tartibga solishi ham mumkin.[55][56]

Amfibiya PGRP-lar amidazalar tomonidan tasdiqlangan yoki bashorat qilingan va ehtimol baliq PGRP-lariga o'xshash funktsiyalarga ega.[4]

Sutemizuvchilardagi ifoda

To'rt sutemizuvchi PGRP ning hammasi ajraladigan oqsillardir.[18][19][57][58]

PGLYRP1 (peptidoglikanni tanib olish oqsili 1 ) barcha sutemizuvchilarning PGRPsining eng yuqori ekspression darajasiga ega. PGLYRP1 yuqori darajada konstruktiv tarzda ifodalangan ilik va granulalarida neytrofillar va eozinofillar, shuningdek, faollashtirilgan makrofaglar, emizikli sut bezlari va ichak Peyerning yamoqlari 'Mikrofold (M) hujayralar va juda kam darajada epiteliy ko'z, og'iz va nafas olish va ichak yo'llarida hujayralar.[6][10][59][60][61][62][63][64][65][66]

PGLYRP2 (peptidoglikanni tanib olish oqsili 2 ) qonda kontsentratsiyali tarzda jigarda ifodalanadi.[10][18][67][68] Jigar PGLYRP2 va undan oldin aniqlangan sarum N-atsetilmuramoyl-L-alanin amidaza bir xil oqsillar bilan kodlangan PGLYRP2 gen.[17][18][58][69] Bakteriyalar va sitokinlar teri va oshqozon-ichak epiteliya hujayralarida PGLYRP2 ekspressionining past darajasini keltirib chiqaradi,[19][68][70][71] ichak intraepitelial T limfotsitlari, dendritik hujayralar, NK (tabiiy qotil ) hujayralar va yallig'lanishli makrofaglar.[72][73] Ba'zi sutemizuvchilar, masalan. cho'chqalar, differentsial ifoda bilan PGLYRP2 ning birlashma shakllarini ifodalaydi.[74]

PGLYRP3 (peptidoglikanni tanib olish oqsili 3 ) va PGLYRP4 (peptidoglikanni tanib olish oqsili 4 ) terida, ko'zda va tarkibida konstruktiv tarzda ifodalanadi shilliq pardalar tilda, tomoq va qizilo'ngach, va ichak traktining qolgan qismlarida ancha past darajada.[10][19][75][76] PGLYRP4 shuningdek tuprik bezlari va mukus - tomoqdagi bezlarni ajratish.[19] Bakteriyalar va ularning mahsulotlari PGLYRP3 va PGLYRP4 ning ifodasini oshiradi keratinotsitlar va epiteliya hujayralari.[19][71] Xuddi shu hujayralarda ifodalanganida, PGLYRP3 va PGLYRP4 hosil bo'ladi disulfid - bog'langan heterodimerlar.[19]

Sichqoncha PGLYRP1, PGLYRP2, PGLYRP3 va PGLYRP4 ham rivojlanayotgan miyada differentsial ravishda namoyon bo'ladi va bu ifoda ichak mikrobiomidan ta'sirlanadi.[77] PGLYRP1 ning ifodasi, shuningdek, kalamush miyasida uyqusizlik tufayli yuzaga keladi[78] va sichqon miyasida ishemiya.[79]

Sutemizuvchilardagi funktsiyalar

Inson PGLYRP1, PGLYRP3 va PGLYRP4 to'g'ridan-to'g'ri Gram-musbat va Gram-salbiy bakteriyalar uchun bakteritsiddir.[19][63][80][81][82][83][84][85][86] Sichqoncha[87][60] va sigir[59][88] PGLYRP1 shuningdek, antibakterial ta'sirga ega va sigir PGLYRP1 ham qo'ziqorinlarga qarshi ta'sirga ega.[59] Ushbu inson PGRPlari bir vaqtning o'zida uchta sinergik stress reaktsiyasini keltirib chiqarish orqali bakteriyalarni yo'q qiladi: oksidlovchi stress, tiol stress va metall stress.[81][83][84][85][86] Ushbu PGRPlar tomonidan bakteriyalarni o'ldirish hujayra membranasini o'tkazuvchanligini, hujayra devorining gidrolizini yoki o'z ichiga olmaydi ozmotik zarba,[19][80][81] lekin bilan sinergetik lizozim[63] va antibakterial peptidlar.[80]

Inson,[18][58] sichqoncha,[57] va cho'chqa go'shti[74] PGLYRP2 fermentlar, N- bakterial hujayra devoridagi peptidoglikan tarkibidagi peptidning peptididagi birinchi aminokislota - MurNAc va L-alanin orasidagi amid bog'lanishini gidrolizlaydigan atsetilmuramoyl-L-alanin amidazalar. PGLYRP2 tomonidan gidrolizlangan minimal peptidoglikan bo'lagi MurNAc-tripeptiddir.[58] PGGYRP2 bilan peptidoglikanning gidrolizi uning yallig'lanishga qarshi faolligini pasaytiradi.[72][89]

Omurgasızlar va pastki umurtqali PGRP'lardan farqli o'laroq, sutemizuvchilar PGRP'lari infektsiyalardan himoyalanishda faqat cheklangan rolga ega. Intranazal PGLYRP3 yoki PGLYRP4 ni sichqonlarga qo'llash intranazal o'pka infektsiyasidan himoya qiladi Staphylococcus aureus va Esherichiya koli,[19][90] va tomir ichiga yuborish orqali PGLYRP1 sichqonlarni tizimdan himoya qiladi Listeriya monotsitogenlari infektsiya.[91] Shuningdek, PGLYRP1- etishmaydigan sichqonlar patogen bo'lmagan bakteriyalar bilan tizimli infektsiyalarga nisbatan sezgirroq (Micrococcus luteus va Bacillus subtilis )[60] va ga Pseudomonas aeruginosa - tushuntirilgan keratit,[64] ammo patogen bakteriyalar bilan tizimli infektsiyalarga emas (S. aureus va E. coli).[60] PGLYRP2- etishmayotgan sichqonlar ko'proq sezgir P. aeruginosa- kelib chiqadigan keratit[92] va Streptokokk pnevmoniya - tushuntirilgan zotiljam va sepsis,[93] va PGLYRP4- etishmayotgan sichqonlar ko'proq sezgir S. pnevmoniya- kelib chiqqan pnevmoniya.[94]

Sichqoncha PGRPlari sog'lom mikrobiomni saqlashda muhim rol o'ynaydi PGLYRP1-, PGLYRP2-, PGLYRP3-, va PGLYRP4-tashqi sichqonlar ichak mikrobiomalari tarkibida sezilarli o'zgarishlarga ega[76][94][95][96] va PGLYRP1- yetishmaydigan sichqonlarning o'pka mikrobiomasida ham o'zgarishlar bo'ladi.[96]

Sichqoncha PGRPlari ichak, terida, o'pkada, bo'g'imlarda va miyada yallig'lanishga qarshi va yallig'lanishga qarshi gomeostazni saqlashda ham rol o'ynaydi.[1][97] Barcha to'rt PGLYRP sichqonlarni dekstran natriy sulfat (DSS) ta'siridan himoya qiladi kolit va PGLYRP2 va PGLYRP3 ning ichak mikrobiomiga ta'siri bu himoya uchun javobgardir.[76][95][98] PGLYRP3 - ichak epiteliya hujayralarida yallig'lanishga qarshi vosita.[99] Sichqoncha modelida PGLYRP4 yallig'lanishga qarshi ta'sirga ega S. pnevmoniya pnevmoniya va sepsis, bu PGLYRP4 tomonidan boshqariladigan mikrobiomga ham bog'liq.[94]

PGLYRP3 va PGLYRP4 yallig'lanishga qarshi va sichqonchani himoya qiladi atopik dermatit[100] va PGLYRP4 shuningdek sichqonlarni himoya qiladi Bordetella yo'tal - nafas yo'llarining yallig'lanishi.[101] PGLYRP2 yallig'lanishga qarshi va sichqonlarni eksperimental ta'siridan himoya qiladi toshbaqa kasalligi - yallig'lanish kabi[102] va Salmonella enterica - ichak yallig'lanishi.[73] Ammo ba'zi PGRPlar teskari ta'sirga ega: PGLYRP2 shuningdek, yallig'lanishga qarshi ta'sirga ega, chunki u eksperimental rivojlanishiga yordam beradi artrit,[103] bakterial ta'sir ko'rsatadigan keratit,[92] va yallig'lanish S. pnevmoniya o'pka infektsiyasi[93] sichqonlarda. PGLYRP1 yallig'lanishga qarshi va eksperimental ta'sirga yordam beradi Astma[65][66] va terining yallig'lanishi[100][102] sichqonlarda va astmaga qarshi bu yallig'lanishga qarshi ta'sir PGLYRP1 tomonidan boshqariladigan ichak mikrobiomiga bog'liq.[96]

PGLYRP1 shuningdek, sichqonlarda eksperimental ravishda kelib chiqqan keratitda yaralarni davolashga yordam beradi [64], PGLYRP2 esa sichqonlarda motor faolligini va tashvishga bog'liq xatti-harakatlarini tartibga soladi.[77][104]

Ba'zi sutemizuvchilarning PGRP-lari mezbon retseptorlari agonistlari yoki antagonistlari sifatida ham ishlashi mumkin. Peptidoglikan yoki multimerizatsiyalangan kompleksli inson PGLYRP1 biriktiruvchi va rag'batlantiruvchi TREM-1 (miyeloid hujayralarda ifodalangan qo'zg'atuvchi retseptor-1), neytrofillarda mavjud bo'lgan retseptor, monotsitlar va yallig'lanishga qarshi sitokinlarni ishlab chiqarishni keltirib chiqaradigan makrofaglar.[105]

Odam va sichqon PGLYRP1 (Tag7) issiqlik zarbasi oqsilini 70 (Hsp70 ) eritmada va PGLYRP1-Hsp70 komplekslari sitotoksik limfotsitlar tomonidan ham ajralib chiqadi va bu komplekslar o'simta hujayralari uchun sitotoksikdir.[106][107] Ushbu sitotoksiklik metastazin bilan antagonizatsiyalanadi (S100A4 )[108] va issiqlikni zarbaga bog'laydigan oqsil HspBP1.[109] PGLYRP1-Hsp70 komplekslari TNFR1 (o'sma nekrozi retseptorlari-1, bu o'lim retseptorlari) va orqali sitotoksik ta'sirni keltirib chiqaradi apoptoz va nekroptoz.[110] Ushbu sitotoksiklik, permeabilizatsiya bilan bog'liq lizosomalar va mitoxondriya.[111] Aksincha, bepul PGLYRP1 TNFR1 bilan bog'lanib, uning PGLYRP1-Hsp70 komplekslari tomonidan faollashishini inhibe qilib, TNFR1 antagonisti vazifasini bajaradi.[110] Odamning PGLYRP1 (163-175 aminokislotalar) peptidi ham sitotoksik ta'sirini inhibe qiladi. TNF-a va PGLYRP1-Hsp70 komplekslari.[112]

Tibbiy ahamiyati

Genetik PGLYRP variantlar yoki PGRPlarning o'zgargan ifodasi bir nechta kasalliklar bilan bog'liq. Bemorlar yallig'lanishli ichak kasalligi (IBD), o'z ichiga oladi Crohn kasalligi va ülseratif kolit, to'rttasida ham tez-tez uchraydigan missense variantlari mavjud PGLYRP sog'lom nazoratdan ko'ra genlar.[113] Ushbu natijalar shuni ko'rsatadiki, PGRPs odamlarni ushbu yallig'lanish kasalliklaridan himoya qiladi va mutatsiyalar PGLYRP genlar ushbu kasalliklarga moyil bo'lgan genetik omillar qatoriga kiradi. PGLYRP1 variantlar ortishi bilan ham bog'liq xomilalik gemoglobin yilda o'roqsimon hujayra kasalligi,[114] PGLYRP2 variantlar qizilo'ngach bilan bog'liq skuamöz hujayrali karsinoma,[115] PGLYRP2, PGLYRP3va PGLYRP4 variantlari bilan bog'liq Parkinson kasalligi,[116] PGLYRP3 va PGLYRP4 variantlar psoriaz bilan bog'liq[117][118] va havo yo'li mikrobiomi,[119] va PGLYRP4 variantlari bilan bog'liq tuxumdon saratoni.[120]

PGLYRP1 ekspressionining ko'payishi bilan bir qator kasalliklar, jumladan: ateroskleroz,[121][122] miokard infarkti, yurak etishmovchiligi,[123] sepsis,[124] o'pka fibrozi,[125] Astma,[126] surunkali buyrak kasalligi,[127] romatoid artrit,[128] gingival yallig'lanish,[129][130][131][132][133] artroz,[134] buyrak transplantatsiyasi bilan og'rigan bemorlarda yurak-qon tomir hodisalari va o'lim,[135] alopesiya,[136] I tip diabet,[137] yuqumli asoratlar gemodializ,[138] va tromboz,[139] PGLYRP1 ning yallig'lanishga qarshi ta'siriga mos keladi. PGLYRP1 ning past ifodasi topilgan endometrioz.[140]

PGLYRP2 ning pasayishi bilan bog'liq OIV - aloqador sil kasalligi,[141] Lyme kasalligi,[142] jigar hujayralari karsinomasi,[143] va miokard infarkti.[144]

Ilovalar

Peptidoglikanni aniqlash uchun ipak qurti lichinkalari plazmasi (SLP) testi, ipak qurti gemolimfasida PGRP tomonidan prophenoloxidase kaskadini faollashtirishga asoslangan, Bombyx mori, mavjud.[145][146]

Shuningdek qarang

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Qo'shimcha o'qish

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Wolf AJ, Underhill DM. Tug'ma immunitet tizimi tomonidan peptidoglikanni tanib olish. Nat Rev Immunol. 2018 yil aprel; 18 (4): 243-254. doi: 10.1038 / nri.2017.136. Epub 2018 yil 2-yanvar. PMID  29292393

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