DSCUSSOKeratglycosylatoprotects from proteover O GlcNAcylatorelated njury Our fndngs demonstrate that ste specfc ablatoof K18 O GlcNAc glycosylatomce results in susceptbty to njury tharelated to STZ or a combned effect of PUGNAc and Fas.Blockng K18 glycosylatodoes not predspose to apoptoss or tssue njury per se but requres another nsult that nhbts O GlcNAcase and therefore rases the ntracellular levels of proteO GlcNAcylaton.Hence, K18 glycosylatoappears to serve like a cytoprotectve and ant apoptoss buffer durng condtons that promote ncreased proteO GlcNAcylaton.The cytoprotectve purpose of K18 glycosylatoappears to be dfferent the lver versus the pancreas snce the ste specfchypophosphorylatoof Akt and PKC that was observed the lver was not observed the pancreas, therefore nvokng orgaspecfc effects of K18 glycosylaton.
The stochometry of K18 glycosylatos estmated for being 2 molecules of O GlcNAc selelck kinase inhibitor per keratmolecule15, whch provdes a potental robust bufferng capacty because of K18 abundance as a key cytoskeletal proteof smple epthela.The bufferng capacty of K18 glycosylatos connected to specfc protens that nclude sgnalng knases and s not a worldwide effect snce not all protens becamehyperglycosylated K18 glycosylatodefcent lver.The K18 glycosylatoprotectve result mce shghly specfc to ths posttranslatonal modfcatosnce mce that overexpress ether the K18 S53A phospho mutant44 or even the K18 R90C mutant that dsrupts the keratfament network ofhepatocytes and renders them markedly susceptble to Fas alone medated apoptoss45 behave smar to WT mce wheexposed to STZ.
Notably, K18 R90C vvo expressoresults hyperglycosylatoof K8 K1846 whch, gvethe fndngsheren, rases the possbty that K18hyperglycosylatomay serve a protectve part that capartally compensate for that effect in the R90C mutaton.addton, the smar susceptbty of K18 WT selleckchem and K18 Gly mce to Fas alone medated njury, contrast wth the dsruptve structural result of K18 R90C okeratcytoplasmc fament organzatoand consequent predspostoto Fas alone medated apoptoss, suggests the K18 Gly mce cytoprotectve phenotype s unlkely for being because of a structural effect with the 3 K18 SerAla mutatons that were ntroduced to nhbt K18 glycosylaton.Even more help for that specfcty of our fndngs s based mostly othe observatothat K18 null mce can also be predsposed to STZ nduced lver pancreatc njury.
how does K18 glycosylatoprovde a cytoprotectve impact O GlcNAcase nhbtounmasks a fresh K18 glycosylatofunctothat protects K18 expressng epthelal tssues

from njury, and lnks glycosylatoof the keratcytoskeletoto actvatoof cell survval knases.Our fndngs assistance a model whereby K18 glycosylatopromotes a phospho Akt pT308 actve state that nhbts cell death.Phospho Akt T308 s lkely to behypoglycosylated snce O GlcNAcase nhbtoby PUGNAc or STZ leads to Akthypophosphorylaton.