Calcium-dependent regulation of the endoplasmic reticulum stress sensor PERK

FERNANDEZ, M; BAIROS, S.; BOLLO, M.

Congreso; XXXV Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2020

SAN

Calcium-dependentregulation of the PERK signaling pathwayFernández M1, Bairos, S. Bollo M11 Instituto de Investigación Médica M y M Ferreyra, INIMEC-CONICET,Universidad Nacional de Córdoba, Córdoba, Argentina.maquifernandez@immf.uncor.edu The endoplasmic reticulum(ER) plays a critical role in a variety of processes, where Ca2+ actsas a key messenger. The accumulation of unfolded proteins into the organelle activatesa signal transduction cascade called Unfolded Protein Response (UPR). An immediateresponse, which attempts to restore homeostasis, is the attenuation of proteinsynthesis due to the activation of PERK, an ER transmembrane kinase,  by auto-phosphorylation.. We demonstrated thatCalcineurin (CN) directly interacts with PERK increasing its activity. Interesting,in astrocytes, CN  has a cytoprotectiveeffect dependent on PERK. In addition, we detected active ER Ca2+ releasethrough the translocon during acute phase of UPR. Although the involvement ofCa2+ signaling in a multitude of cellular functions has been welldocumented, littleis known about its role in restoring homeostasis, once UPR is activated. Here,we evaluated the dependence of Ca2+ on PERK phosphorylation by immunocytochemistryand we analyzed PERK/CN interaction, after induces stress and pharmacologicallymodify translocon activity. This was further studied by using a cell line deficientin all isoforms of IP3 receptor. Moreover, we demonstrated that,PERK forms a macromolecular complex with translocon pore (Sec61a) and CN by performing a blue native PAGE followedby a second dimensional gels.  Overall, thesedata strongly suggest that PERK is activated by Ca2+ signaloriginated through the translocon during acute phase of UPR. @font-face{font-family:"MS Mincho";panose-1:2 2 6 9 4 2 5 8 3 4;mso-font-alt:"ＭＳ 明朝";mso-font-charset:128;mso-generic-font-family:modern;mso-font-pitch:fixed;mso-font-signature:-536870145 1791491579 134217746 0 131231 0;}@font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:swiss;mso-font-pitch:variable;mso-font-signature:-536859905 -1073732485 9 0 511 0;}@font-face{font-family:"\@MS Mincho";panose-1:2 2 6 9 4 2 5 8 3 4;mso-font-charset:128;mso-generic-font-family:modern;mso-font-pitch:fixed;mso-font-signature:-536870145 1791491579 134217746 0 131231 0;}p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}a:link, span.MsoHyperlink{mso-style-priority:99;color:#0563C1;mso-themecolor:hyperlink;text-decoration:underline;text-underline:single;}a:visited, span.MsoHyperlinkFollowed{mso-style-noshow:yes;mso-style-priority:99;color:#954F72;mso-themecolor:followedhyperlink;text-decoration:underline;text-underline:single;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:11.0pt;mso-ansi-font-size:11.0pt;mso-bidi-font-size:11.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}.MsoPapDefault{mso-style-type:export-only;margin-bottom:8.0pt;line-height:107%;}div.WordSection1{page:WordSection1;}