S-Space College of Natural Sciences (자연과학대학) Dept. of Biological Sciences (생명과학부) Theses (Ph.D. / Sc.D._생명과학부)
A study on the essential role of casein kinase gamma 1 and 3 in necroptosis
세포괴사 조절 인자로서 카제인 키나아제 1 감마에 대한 연구
- 자연과학대학 생명과학부
- Issue Date
- 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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