A study on the essential role of casein kinase gamma 1 and 3 in necroptosis
세포괴사 조절 인자로서 카제인 키나아제 1 감마에 대한 연구

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자연과학대학 생명과학부
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서울대학교 대학원
학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 생명과학부, 2018. 8. 정용근.
Upon necroptosis activation, receptor interacting serine/threonine kinase

(RIPK) 1 and RIPK3 form a necrosome complex with pseudokinase mixed

lineage kinase-like (MLKL). Although protein phosphorylation is a key

event for the activation of RIPK1 and RIPK3 in response to necroptosis

signal, relatively little is known about other factors that can regulate the

activity of those kinases or necrosome formation. In a gain-of-function

screen with 650 kinases and 120 phosphatases, I identified that casein

kinase 1 gamma (CK1γ) as a crucial regulator of necroptosis. Here I show

that the downregulation of CK1γ1 and CK1γ3, either by a chemical

inhibitor or knockdown in cells, reduced TNFα-induced necroptosis.

Conversely, ectopic expression of CK1γ1 or CK1γ3 exacerbated

necroptosis, but not apoptosis. Like RIPK1 and RIPK3, CK1γ1 was

cleaved at Asp434 by caspase-8 during apoptosis, while it was increased in

response to necroptosis. CK1γ1 and CK1γ3 formed a protein complex with

each other and were recruited into the necrosome harboring RIPK1, RIPK3

and MLKL. Especially, autophosphorylated form of CK1γ3 at Ser344/345

was detected in the necrosome and was required to mediate the necroptosis.

In addition, CK1γ phosphorylates RIPK3 in vitro and a CK1γ-specific

inhibitor Gi reduced the phosphorylation of MLKL at Ser358, as well as

the formation of MLKL oligomers, and rescued mice from TNFα-induced

systemic inflammatory response syndrome (SIRS). Collectively, these data

suggest that CK1γ1 and CK1γ3 are required for promoting cell death

progression by regulating the formation of necrosome through RIPK3.
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College of Natural Sciences (자연과학대학)Dept. of Biological Sciences (생명과학부)Theses (Ph.D. / Sc.D._생명과학부)
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