Молекулярно-генетические пути регуляции вирусом гепатита С экспрессии клеточных факторов PREB и PLA2G4C, играющих важную роль для репликации вируса

В репликации генома вируса гепатита С (ВГС) участвуют как вирусные, так и хозяйские белки. Терапевтические подходы, основанные на подавлении активности неструктурных вирусных белков NS3, NS5A, NS5B, проходят клинические испытания разных уровней. Однако быстрые мутационные процессы вирусного генома и приобретение лекарственной устойчивости остаются одними из главных препятствий в борьбе с ВГС. 

Идентификация и исследование клеточных факторов, участвующих в репликации РНК ВГС, а также регуляция вирусом их экспрессии важны для понимания механизмов репликации вируса и разработки эффективных подходов противовирусной терапии. Известно, что белок PREB, связывающий регуляторный элемент пролактина, и цитозольная фосфолипаза А2 гамма (PLA2G4C) играют важную роль в формировании платформ репликации РНК ВГС, а также в функционировании вирусной репликазы. Экспрессия генов PREB и PLA2G4C значительно увеличена в присутствии ВГС, но механизмы ее регуляции вирусными белками до сих пор не изучены. В данной работе с применением технологии текст-майнинга, реализованной в программно-информационной системе ANDSystem, реконструированы генные сети регуляции экспрессии генов человека PREB и PLA2G4C белками ВГС. На основании анализа генных сетей мы выдвинули гипотезы о регуляторных эффектах белков ВГС на функции хозяйских факторов в результате белок-белковых взаимодействий. Среди вирусных белков наибольшее количество регуляторных связей выявлено у вирусной протеазы NS3. Предположительно NS3 в результате белок-белкового взаимодействия подавляет активность транскрипционного фактора NOTCH1, что обусловливает активацию экспрессии PREB и PLA2G4C. Анализ генных сетей и данных о дифференциальной экспрессии генов в присутствии ВГС позволил нам также выдвинуть гипотезы о регуляции вирусом экспрессии транскрипционных факторов, сайты связывания которых находятся в районах генов PREB и PLA2G4C, и действии этих транскрипционных факторов на регуляцию транскрипции PREB и PLA2G4C. Полученные результаты могут быть использованы при планировании исследований по изучению молекулярно-генетических механизмов взаимодействия вирус–хозяин и поиска потенциальных мишеней для разработки лекарств против ВГС.

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