Роль трансглутаминазы 2 в регуляции баланса между аутофагией и апоптозом в опухолевых клетках

В нормальной ткани клеточный гомеостаз в значительной степени обусловлен двумя катаболическими путями: апоптозом и аутофагией. Апоптоз, или запрограммированная клеточная гибель, регулируется проапоптотическими факторами и способствует уничтожению поврежденных клеток. Аутофагия, в свою очередь, включающая в себя 3 формы – макро-, микро- и шаперон-опосредованную аутофагию, – может как способствовать выживанию клеток путем избирательного  удаления факторов, потенциально вызывающих апоптоз, так и повышать порог стресса, необходимого для индукции клеточной гибели. В последнее время накапливаются данные, свидетельствующие о существовании общих молекулярных путей между аутофагией и апоптозом, а также о влиянии каспазного матрикса на данные процессы.  Одним из важных ферментов, участвующих в координации и регуляции этих процессов, является трансглутаминаза 2 (TG2). Различные типы активностей TG2 вовлечены в поддержание динамического баланса между внутриклеточным матриксом и внутриклеточными процессами аутофагии/апоптоза, в то время как их дерегуляция может способствовать развитию патогенеза различных заболеваний человека, включая онкогенез. Например, известно, что TG2 может благоприятствовать деградации проапоптотических белков и выживанию клеток почечно-клеточной карциномы в условиях недостатка питательных веществ, модулируя процесс аутофагии. В клетках различных тканей, лишенных TG2, наблюдается скопление агрегатов убиквитинированных белков и поврежденных митохондрий, что вызывает протеотоксический стресс и клеточную смерть. Наоборот, трансамидазная активность TG2 была замечена в ингибировании антиапоптотических сигналов на модели лейкемической моноцитарной лимфомы человека. В данном обзоре описываются важные функции TG2 в онкогенезе, а также подчеркивается двойственность роли этого фермента в модуляции таких противоположных процессов, как выживание клеток и их гибель.

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