New gene seg­ment dis­cov­ery has po­ten­tial against cancer, au­toim­mune dis­or­ders

Big Spring Herald - - LOCAL/STATE - Spe­cial to the Her­ald

COL­LEGE STA­TION – A small seg­ment of a hu­man gene STING, stim­u­la­tor of in­ter­feron genes, could hold the key to treat­ing au­toim­mune dis­eases and cancer, ac­cord­ing to a study by Texas A&M AgriLife Re­search sci­en­tists.

Dr. Ping­wei Li, AgriLife Re­search bio­chemist and struc­tural bi­ol­o­gist, Col­lege Sta­tion; post doc­tor­ates Drs. Baoyu Zhao, and Fen­glei Du and grad­u­ate stu­dent Peng­biao Xu, Col­lege Sta­tion, dis­cov­ered a pro­tein mo­tif that could en­able fu­ture ap­plied science re­searchers to de­velop drugs to sup­press un­wanted im­mune re­sponses in hu­mans that cause au­toim­mune dis­or­ders.

Their re­search, “A con­served PLPLRT/SD mo­tif of STING me­di­ates the re­cruit­ment and ac­ti­va­tion of TBK1,” was pub­lished in the May 30 is­sue of the in­ter­na­tional sci­en­tific jour­nal Na­ture.

STING are pro­teins that sig­nal im­mune re­sponses in hu­mans and other an­i­mals, Li said. The PLPLRT/SD mo­tif the sci­en­tists dis­cov­ered is a short stretch of amino acids near the end of the STING pro­tein that plays a crit­i­cal role in turn­ing on the im­mune sys­tem to fight against vi­ral in­fec­tions.

TBK1 is a pro­tein ki­nase as­so­ci­ated with dis­eases like fron­totem­po­ral de­men­tia, some can­cers and au­toim­mune dis­eases like Lu­pus, Li said. The Li lab iden­ti­fied a short se­quence in the pro­tein STING that re­cruits and ac­ti­vates TBK1, thus turn­ing on the im­mune re­sponse.

The sci­en­tists found that a con­served PLPLRT/SD mo­tif within the C-ter­mi­nal tail of STING me­di­ates the bind­ing of TBK1, Li said. This demon­strates the di­rect bind­ing be­tween STING and TBK1 is es­sen­tial for STING me­di­ated sig­nal­ing.

“Our im­mune sys­tem is like an elec­tri­cal cir­cuit,” he said. “We dis­cov­ered that this mo­tif of STING is in­volved in the ac­ti­va­tion of the TBK1, essen­tially like a switch that turns the im­mune sys­tem on to pro­duce in­ter­fer­ons to fight against vi­ral in­fec­tions or cancer.”

Li’s re­search was ini­tially funded for three years via a nearly $1 mil­lion grant from the Cancer Pre­ven­tion and Re­search In­sti­tute of Texas, or CPRIT. Re­cently, he re­ceived an­other $1.8 mil­lion in fund­ing from the Na­tional In­sti­tute of Health through the Na­tional In­sti­tute of Al­lergy and In­fec­tious Dis­eases to con­tinue their stud­ies about the an­tivi­ral im­mune re­sponse for the next five years.

The team of sci­en­tists de­ter­mined the crys­tal struc­ture of TBK1 bound to STING re­veals the de­tailed molec­u­lar in­ter­ac­tions be­tween these two pro­teins. They used a very pow­er­ful X-ray beam pro­duced by the Ad­vanced Light Source at the Lawrence Berke­ley Na­tional Lab­o­ra­tory of the Uni­ver­sity of Cal­i­for­nia to col­lect high-qual­ity dif­frac­tion data, Li said.

These find­ings pro­vide a ba­sis for fu­ture sci­en­tific in­quiry and de­vel­op­ment of STING binder and blocker drugs in the fight against vi­ral in­fec­tion, cancer and au­toim­mune dis­or­der, Li said. It’s a seem­ingly small dis­cov­ery in ba­sic re­search, but one that could have enor­mous im­pli­ca­tions re­gard­ing the way dis­eases are treated in the fu­ture.

Li said there are in­cred­i­ble in­ter­ests in the phar­ma­ceu­ti­cal in­dus­try to iden­tify new ways to block TBK1 ac­ti­va­tion to con­trol un­wanted, harm­ful im­mune re­sponses.

“We con­ducted the ba­sic re­search, and oth­ers will fol­low with ap­plied re­search on what we dis­cov­ered,” he said. “There is still a lot that is un­known, but to play a part in re­search with so much po­ten­tial to treat cancer and de­bil­i­tat­ing au­toim­mune dis­eases is very grat­i­fy­ing.”

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