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UID:1783598400@ist.ac.at
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DESCRIPTION:Speaker: David Michalik\nhosted by Eva Benková\nAbstract: MDA5
  is an antiviral protein that is activated by long dsRNA molecules. This R
 NA can be of various origins such as viral\, bacterial\, synthetic or\, up
 on certain stimuli\, even cellularsources. Upon sensing immunogenic RNA\, 
 MDA5 coats the dsRNA\, forming a filament. Filament formation brings CARD 
 domains into close proximity\, resulting in CARD oligomerisation. These ol
 igomers are not involved in the RNA recognition but are crucial for activa
 tion of downstream signalling. MDA5 activation leads to a type I interfero
 n response and apoptosis. Loss of function mutations are linked to recurre
 nt\, life-threatening viral infections whereas gain of function mutations 
 are linked to monogenic and polygenic autoimmune diseases. For these reaso
 ns\, MDA5 needs to be tightly regulated by various mechanisms including po
 st-translational modifications\, post-transcriptional modifications\, and 
 protein-protein interactions. In the first chapter\, we focused on the cha
 racterisation of novel phosphorylation sites in MDA5. Using biochemistry\,
  molecular dynamics simulations\, virology\, cell biology and mass spectro
 metry\, we characterised two phosphorylation sites that altered MDA5 activ
 ity andwere regulated in cells upon EMCV infection or IFN-β treatment. Fu
 rthermore\, we discovered an additional phosphorylation site in a non-cons
 erved region\, which is upregulated under both stimuli.In the second chapt
 er\, we focused on biochemical\, biophysical\, and structural characterisa
 tion of various RNAs and MDA5 filaments assembled on them. We discovered t
 hat poly I:C\, a synthetic RNA used to activate an immune response in cell
 s\, has distinct physicochemical characteristics and is not a true mimic o
 f viral RNA\, as is often described. Additionally\, we used cryogenic elec
 tron microscopy to gain structural insights into which RNA features define
  a strong activator of MDA5. To address this\, we compared poly I:C to pol
 y A:U\, an RNA that does not activate an MDA5 signalling in cells\, and to
  a virus-derived dsRNA. In the last chapter\, we focused on activators of 
 MDA5 signalling. In the first part\, we present our efforts to isolate and
  identify a small molecule agonist of MDA5. In the last part\, we describ
 ed our contribution to a collaborative project during which we characteris
 ed the interaction of ANXA2 with MDA5 and activation of MDA5 by a small mo
 lecule.
LOCATION:Sunstone Bldg / Ground floor / Big Seminar Room B / 63 seats (I23.
 EG.102)\, ISTA
ORGANIZER:
SUMMARY:David Michalik: Thesis Defense: Mechanistic insights into MDA5 sele
 ctivity and regulation
URL:https://talks-calendar.ista.ac.at/events/6508
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