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dc.contributor.advisorStarheim, Kristian K. - Bjørkøy, Geir
dc.contributor.authorBhandari, Madhavi
dc.date.accessioned2019-09-06T14:02:31Z
dc.date.available2019-09-06T14:02:31Z
dc.date.issued2019
dc.identifier.urihttp://hdl.handle.net/11250/2613177
dc.description.abstract
dc.description.abstractSQSTM1 is a cytosolic protein important for collecting ubiquitinated proteins and organelles for degradation, but its function as a scaffold protein in forming multimer signaling complexes is not completely elucidated. A previous study found that SQSTM1 interacts with RIPK1 in TNF-induced NF-B signaling pathway. RIPK1is a key molecule in TNFR1 signaling that can either lead to inflammation and cell survival or cell death in hematopoietic cells. RIPK1 activity is extensively regulated by ubiquitination which also enable it to function as a scaffold. Preliminary proteomics study from our group found that TRIM25, a ubiquitin ligase, interacts with RIPK1 in mouse macrophages. The TRIM25-RIPK1 interaction was conserved in LPSprimed human macrophages as well. Besides, the study also identified TRIM25 as an interaction partner of SQSTM1. Considering these interconnections, we hypothesized that SQSTM1, TRIM25 and RIPK1 interact to regulate RIPK1 signaling in human macrophages. Our findings from co-immunoprecipitation studies confirmed a basal, TNF-independent interaction between SQSTM1, TRIM25 and RIPK1 in unprimed THP-1 cells. The CRISPRCas9 mediated knockdown of SQSTM1 led to an increase in TNF-induced IL-8 while decrease in IL-10 secretion levels. TNF stimulation of TRIM25 knockdown cells showed an increase in IL-8 secretion level. In summary, the data presented suggests that SQSTM1, TRIM25 and RIPK1 might form a multi-protein complex that has functional roles in TNF-mediated RIPK1 signaling in human macrophages.
dc.languageeng
dc.publisherNTNU
dc.titleSQSTM1 interacts with TRIM25 and RIPK1 in TNF signaling
dc.typeMaster thesis


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