Amino acids yog cov ntsiab lus tseem ceeb ntawm cov protein thiab cov khoom tseem ceeb ntawm tib neeg cov ntaub so ntswg, ua si lub luag haujlwm ntawm kev hloov pauv ntawm tes, kev tswj hwm enzyme, kev tiv thaiv kab mob thiab lwm yam haujlwm ntawm lub cev.

Qhov ntau ntawm cov amino acids nyob rau hauv cov hlwb feem ntau hloov nyob rau hauv txawv physiological thiab pathological xeev. Yog li ntawd, yuav ua li cas lub cev paub qhov kev hloov ntawm cov amino acid theem thiab ua rau ib tug adaptive teb yog ib qho tseem ceeb scientific teeb meem ntawm metabolic kev nyuaj siab thiab cell destiny.

Qhov txawv txav ntawm amino acid sensing yog ze ze rau mob qog noj ntshav, ntshav qab zib, kab mob neurodegenerative thiab txheej txheem kev laus. Yog li, kev tshawb nrhiav cov txheej txheem molecular ntawm qhov txawv txav amino acid induction yuav muab lub hom phiaj tshiab rau kev tiv thaiv lossis kho cov kab mob metabolic thiab mob qog noj ntshav. Valine, raws li ib qho tseem ceeb branched-chain amino acid, plays lub luag hauj lwm tseem ceeb hauv protein synthesis, neurobehavior, thiab leukemia kev loj hlob. Txawm li cas los xij, cov txheej txheem thiab kev ua haujlwm ntawm cellular sensing ntawm valine tseem tsis meej.

Thaum Lub Kaum Ib Hlis 20, 2024, Wang Ping pab pawg los ntawm Tongji University Tsev Kawm Ntawv Tshuaj Kho Mob / 10th Affiliated People's Hospital tau luam tawm cov ntawv tshawb fawb hu ua "Human HDAC6 senses valine abundancy to regulate DNA damage" in the journal Nature.

Txoj kev tshawb no tau txheeb xyuas qhov tshiab valine-specific sensor, tib neeg deacetylase HDAC6, thiab qhia txog cov txheej txheem tshwj xeeb los ntawm kev txwv valine ua rau muaj kev hloov pauv hauv nuclear ntawm HDAC6, yog li txhim kho TET2 kev ua haujlwm thiab ua rau DNA puas.

Interestingly, qhov kev hnov ????mob no yog tshwj xeeb rau cov tsiaj txhu, thiab kev tshuaj xyuas ntxiv tau qhia tias primate HDAC6 muaj cov serine-nplua nuj glutamate-tetranectide (SE14) rov ua dua thiab hnov ????valine abundance los ntawm lub npe no. Hais txog kev kho mob qog noj ntshav, kev txwv tsis pub muaj valine lossis kev sib xyaw ntawm PARP inhibitors tuaj yeem cuam tshuam cov qog loj hlob.

Txoj kev tshawb no nthuav tawm cov txheej txheem tshiab los ntawm kev noj zaub mov kev ntxhov siab tswj hwm DNA kev puas tsuaj los ntawm kev hloov pauv hauv epigenetic, thiab nthuav tawm lub tswv yim tshiab rau kev kho mob qog noj ntshav nrog kev noj zaub mov txwv tsis pub noj nrog PARP inhibitors.

Amino acid sensors feem ntau yuav tsum tau muab cov amino acids sib xyaw kom paub txog thiab teb rau cov kev hloov pauv ntawm cov amino acid concentration sab hauv thiab sab nraud ntawm tes, txhawm rau ua lawv qhov kev paub.

Txhawm rau txhawm rau txheeb xyuas cov kab mob valine-binding proteins, biotinylated valine probes tau siv rau kev sim tshuaj immunocoprecipitate ua ke nrog pawg spectrometry, thiab kev tshuaj xyuas tsis ncaj ncees ntawm valine-binding proteins tau ua los ntawm tshuaj lom neeg biology.

Cov kws sau ntawv pom tias ntxiv rau qhov paub txog valyl tRNA synthetases (VARS), deacetylase HDAC6 tau pom tias muaj zog D-valine binding muaj peev xwm piv rau VARS. Cov kws sau ntawv tau lees paub ntxiv tias HDAC6 tuaj yeem khi ncaj qha rau valine nrog kev sib raug zoo ntawm Kd ≈ 2μM los ntawm isotope binding thwmsim, isothermal titration calorimetry (ITC) thwmsim thiab thermal drift thwmsim. Kev tsom xam ntawm cov yam ntxwv ntawm cov amino acids lees paub los ntawm kev hnov ????cov proteins yog pab kom nkag siab ntxiv txog cov txheej txheem molecular ntawm kev hloov pauv ntawm amino acid abundance induced los ntawm cov hlwb. Los ntawm kev txheeb xyuas qhov kev sim ua ke ntawm valine analogues, cov kws sau ntawv pom tias HDAC6 lees paub lub carboxyl davhlau ya nyob twg thiab sab saw ntawm valine thiab tuaj yeem zam qhov kev hloov pauv ntawm cov amino terminal. Tsis tas li ntawd, nyob rau hauv HDAC6 knockout hlwb, cov kev cai ntawm mTOR teeb liab txoj kev los ntawm valine txwv tsis muaj qhov sib txawv ntawm pawg tswj hwm, qhia tias qhov kev khi no txawv ntawm cov tshuaj amino acid sensing signaling pathway.

Txhawm rau tshawb nrhiav qhov tseem ceeb thiab kev ua haujlwm ntawm HDAC6 sensing valine. Cov kws sau ntawv tau txiav txim siab ntxiv tias HDAC6 khi valine los ntawm nws qhov SE14 sau los ntawm HDAC6 truncated body binding test. Kuj ceeb tias, cov kws sau ntawv pom los ntawm kev sib piv homology uas SE14 sau tsuas yog tam sim no hauv HDAC6 hauv primates. Tsis zoo li primate (tib neeg thiab liab) HDAC6, nas HDAC6 tsis khi rau valine. Qhov kev tshawb pom no qhia txog qhov sib txawv ntawm cov tsiaj sib txawv hauv valine induction, qhia tias hom evolution plays lub luag haujlwm tseem ceeb hauv amino acid induction.

Raws li qhov xaus tias HDAC6 ncaj qha khi valine los ntawm nws lub npe SE14, cov kws sau ntawv tau kwv yees tias kev hloov pauv hauv kev khi lub zog ntawm HDAC6 thiab valine tuaj yeem cuam tshuam rau nws cov qauv thiab kev ua haujlwm thaum muaj ntau ntawm valine hauv hlwb hloov. Los ntawm ntau qhov kev sim thiab ua ke nrog cov ntaub ntawv ntawm lub luag haujlwm tseem ceeb ntawm SE14 sau hauv cytoplasmic retention ntawm HDAC6, cov kws sau ntawv pom tias intracellular valine deficiency tuaj yeem ua rau HDAC6 hloov mus rau lub nucleus. Lub enzyme active cheeb tsam (DAC1 thiab DAC2) khi rau thaj tsam nquag (CD sau) ntawm DNA hydroxymethylase TET2, txhawb kev deacetylation ntawm TET2, thiab tom qab ntawd ua kom nws cov enzyme ua haujlwm. Siv cov txheej txheem methylomics xws li WGBS, ACE-Seq thiab MAB-Seq, peb tau lees paub ntxiv tias kev tshaib plab intracellular valine tuaj yeem txhawb nqa DNA demethylation los ntawm HDAC6-TET2 teeb liab axis. Yav dhau los, Andre Nussenzweig pab pawg pom tias thymine DNA glycosylase (TDG) -dependent active DNA demethylation ua rau DNA ib leeg-strand puas tsuaj rau neuronal enhancer. Los ntawm kev sib txuas TET2 Chip-Seq nrog high-throughput sequencing technology END-Seq thiab ddC S1 END-Seq, peb txiav txim siab tias valine deficiency txhawb DNA puas. Qhov kev puas tsuaj DNA tshwm sim los ntawm valine deficiency kuj yog nyob ntawm ib qho kev puas tsuaj los ntawm TDG excision ntawm oxymethylcytosine (5fC / 5caC).

Ua ke, cov kws sau ntawv tau tshawb pom cov tshiab valine sensors thiab thawj zaug elucidated lub tshuab molecular los ntawm valine txwv qhov kev cuam tshuam ntawm DNA kev puas tsuaj los ntawm HDAC6-TET2-TDG signaling axis, ntxiv qhov tshiab rau kev nkag siab txog kev ua haujlwm ntawm amino acid kev nyuaj siab hauv kev txiav txim siab txoj hmoo ntawm tes.

Kev txwv kev noj haus lossis kev tsom xam ntawm cov amino acid metabolism thiab kev hnov ????qab tau dhau los ua lub tswv yim ntxiv rau lub neej txuas ntxiv thiab kho ntau yam kab mob, suav nrog mob qog noj ntshav. Muab hais tias valine deprivation tuaj yeem ua rau muaj kev puas tsuaj DNA, cov kws sau ntawv tau tshawb xyuas ntxiv seb qhov kev txwv valine plays lub luag haujlwm hauv kev kho mob qog noj ntshav. Hauv cov qauv qog nqaij hlav qog nqaij hlav qog nqaij hlav, kev noj zaub mov tsis zoo valine (0.41% valine, w / w) cuam tshuam cov qog loj hlob nrog tsawg dua cov kev mob tshwm sim. Hauv ob pawg kev tiv thaiv thiab kev kho mob, cov kws sau ntawv tau qhia ntxiv tias kev noj zaub mov tsis muaj valine inhibited qog nqaij hlav thiab kev loj hlob siv tus qauv mob qog noj ntshav PDX. Hauv cov qauv qog, cov qib valine txo qis tau zoo cuam tshuam nrog nce HDAC6 nuclear translocations, qib 5hmC, thiab DNA puas. Txij li thaum inducing DNA puas yog ib qho kev kho mob anticancer, nws muaj peev xwm kho DNA kho los ntawm kev siv PARP inhibitors. Cov kws sau ntawv pom tias kev sib xyaw ntawm valine txwv kev noj zaub mov thiab PARP inhibitor talazoparib tau txhim kho cov nyhuv antitumor, muab pov thawj muaj zog rau kev kho mob qog noj ntshav los ntawm kev ua rau DNA puas.

Hauv kev xaus, txoj kev tshawb fawb pom tias HDAC6 hauv primates yog ib qho tshiab valine sensing protein ywj siab ntawm cov tshuaj ib txwm muaj, qhia qhov sib txawv ntawm valine sensing ntawm ntau hom, qhia txog lub luag haujlwm tseem ceeb ntawm kev hloov pauv lom neeg hauv amino acid sensing.

Tsis tas li ntawd, txoj kev tshawb no nthuav tawm cov txheej txheem tshiab ntawm kev sib tham sib tswj hwm ntawm kev noj zaub mov tsis txaus siab, kev tswj hwm epigenetic thiab DNA puas tsuaj, nthuav dav qhov tseem ceeb ntawm kev noj haus metabolic kev ntxhov siab hauv biology kev ntxhov siab, thiab pom tias kev sib xyaw ntawm valine txwv kev noj zaub mov thiab PARP inhibitors tuaj yeem siv los ua lub tswv yim tshiab rau kev kho mob qog noj ntshav.