Universität zu Köln

Körner, Lioba Katharina (2022). Cell death and inflammation in skin homeostasis and small cell lung cancer. PhD thesis, Universität zu Köln.

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Abstract

Z-DNA binding protein 1 (ZBP1) has evolved as a key player in viral infections and tissue homeostasis promoting necroptotic cell death. Whilst a RHIM-RHIM dependent interaction between ZBP1 and RIPK1 has been implicated to exert inhibitory functions, RHIM-mediated recruitment of RIPK3 to ZBP1 was shown to induce necroptosis. In this work, we firstly show that TNFR1 and ZBP1 act synergistically to trigger skin inflammation upon keratinocyte-specific loss of FADD, reinforcing ZBP1 as a crucial player in skin homeostasis. We then aimed to shed light on the mechanisms of ZBP1 downstream signaling in presence of RIPK1 and FADD, as most studies thus far dissecting ZBP1 signaling in vivo required loss of one of these two proteins. To this aim we generated a constitutively active C-terminally truncated version of ZBP1 (ZBP1ca). Keratinocyte-specific ZBP1ca expression was able to induce apoptosis as well as necroptosis dependent on RIPK1 and RIPK3 RHIM-RHIM interactions, respectively. Mechanistically, this RIPK1-mediated apoptosis appeared to be independent of its kinase activity, identifying a novel mechanism of ZBP1-driven cell death. Having established ZBP1ca as a potent inducer of inflammation, we aimed to make use of this construct in a therapeutic setting. To this end, we utilized a mouse model for small cell lung cancer (SCLC), the most aggressive lung cancer subtype, which is in urgent need for novel targeted therapies. Our data suggest resistance of a subset of SCLC cell lines to the induction of immunogenic cell death by MLKL activation, further warranting the close investigation of molecular mechanisms underlying this deadly disease. Using different genetically modified mouse models investigating the role of inflammatory signaling in SCLC, we observed a strong dependency on NEMO/RelA-dependent NF-kB signaling for SCLC development, suggesting inhibition of NF-kB signaling as a therapeutic option for SCLC. Taken together, our study highlights a novel mechanism for ZBP1-induced cell death in sterile conditions and gives new insights about ZBP1-mediated signaling. Furthermore, we present data which can aid in the treatment of SCLC as human patients may benefit from NF-kB inhibition.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Körner, Lioba Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-653829
Date:	19 December 2022
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Natural sciences and mathematics Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language ZBP1 UNSPECIFIED Inflammation UNSPECIFIED Cell death UNSPECIFIED Lung Cancer UNSPECIFIED SCLC UNSPECIFIED NF-kB UNSPECIFIED
Date of oral exam:	14 February 2023
Referee:	Name Academic Title Pasparakis, Manolis Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/65382