Cенсоры внутриклеточных нуклеиновых кислот, активирующие STING-зависимую продукцию интерферонов в иммунокомпетентных клетках

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В настоящее время белки-сенсоры чужеродной ДНК или РНК, играющие важную роль во врожденном иммунитете, вызывают большой интерес как новый способ иммунотерапии рака. Агонисты этих белков способны активировать в иммунных клетках сигнальные каскады, вызывающие продукцию цитокинов, в частности интерферонов I типа, обладающих мощным цитотоксическим эффектом. В обзоре рассмотрено функционирование цитоплазматических сенсоров нуклеиновых кислот, таких как cGAS, STING, IFI16, AIM2, DAI, DDX41, DNA-PK, MRE-11, TREX1, участвующих в активации продукции различных цитокинов.

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Л. В. Смольянинова

НИИ Экспериментальной диагностики и терапии опухолей, НМИЦ онкологии им. Н. Н. Блохина Минздрава России

Email: smolyaninovalarisa1@gmail.com
Россия, Москва, 115478

О. Н. Солопова

НИИ Экспериментальной диагностики и терапии опухолей, НМИЦ онкологии им. Н. Н. Блохина Минздрава России

Автор, ответственный за переписку.
Email: smolyaninovalarisa1@gmail.com
Россия, 115478, Москва

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2. Рис. 1. Цитоплазматические сенсоры нуклеиновых кислот, участвующие в активации STING сигнального пути и вызывающие продукцию интерферонов I типа.

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3. Рис. 2. Схема доменной организации cGAS человека (а) и модель комплекса cGAS–ДНК (2:2) (б), в составе которого каждый мономер cGAS взаимодействуют с ДНК (адаптировано из [10, 11], используется с разрешения издательства).

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4. Рис. 3. Схема доменной организации белка человека STING (а) и модель комплекса лиганд–STING (б) (адаптировано из [27], используется с разрешения издательства).

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5. Рис. 4. Схема доменной организации белка IFI16 мыши (а) и модель комплекса дцДНК с HINa- и HINb-доменами, связанными между собой линкером (красный цвет) (б) (адаптировано из [51], используется с разрешения издательства).

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6. Рис. 5. Схема доменной организации AIM2 (а) и модель структуры PYD-домена (лимонный цвет) и комплекса дцДНК–AIM2 (б) (адаптировано из [63], используется с разрешения издательства). OB1, OB2 — олигонуклеотид/олигосахарид связывающие складки в составе HIN200-домена.

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7. Рис. 6. Схема доменной организации ZBP1 (а) и модель структуры комплекса Z-ДНК c двумя молекулами ZBP1 (б) (адаптировано из [71, 74], используется с разрешения издательства). а — Розовым показаны Zα- и Zβ-домены, связывающие Z-форму ДНК; желтым показан D3-регион, участвующий в связывании правозакрученной В-формы ДНК. б — дцДНК (коричневый цвет), молекулы ZBP1 (фиолетовый цвет).

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8. Рис. 7. Схема доменной организации DDX41 (а), модель структуры закрытой конформации DEAD-домена (б) и докинг модель комплекса DEAD-домена, связанного с дцДНК (в) (адаптировано из [85, 86], используется с разрешения издательства).

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9. Рис. 8. Схема доменной организации DNA-PKcs (а) и субъединиц Ku70, Ku80 человека (б), модель вторичной структуры димерного комплекса субъединиц Ku80 (фиолетовый цвет) и Ku70 (красный цвет) (в) и комплекса ДНК (желто-оранжевый цвет) с гетеродимером Ku70–Ku80 (г) (адаптировано из [94–96], используется с разрешения издательства). Аминокислота, после которой начинается специфичная для субъединицы Ku70 аминокислотная последовательность, отмечена голубой заполненной точкой.

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10. Рис. 9. Схема доменной организации MRE-11 (а) и модель комплекса E. coli MRE11–RAD50 в состоянии покоя (б) и в связанном с ДНК состоянии (в) (адаптировано из [102, 103], используется с разрешения издательства). Связывание ДНК вызывает сдвиг в нуклеотид-связывающих доменах (NBD) и перестройки в MRE-11, что приводит к формированию канала в области активных центров и зажиму концов ДНК. HLH — спираль-петля-спираль, CC — двойная спираль.

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11. Рис. 10. Схема доменной организации TREX1 (а) и модель структуры гомодимера TREX1 (б) (адаптировано из [106, 107], используется с разрешения издательства). б — Мономеры TREX1 обозначены голубым и фиолетовым цветами. Черным квадратом выделена область активного центра, где связываются ионы магния (зеленые сферы) и нуклеотид dТМP (желто-оранжевая структура), а также происходит связывание оцДНК. В составе мономера присутствует неупорядоченная петля (166–174 а. о.), принимающая участие в связывании с дцДНК. Положение петли обозначено Ala165 и Lys175.

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