Lecture 5 - Exam 1 Flashcards
(29 cards)
What is NF-kB responsible for?
It is a transcription factor that acts as a central regulator in the stress response in inflammation, anti-apoptosis and proliferation/survival (cancer), and many others - how we sense microbes (toll like receptors - TLRs)
What are the 4 key elements for NF-kB?
Some type of receptor, IKK complex (kinase), IkB inhibitor proteins, NF-kB dimer itself
What are the 5 members of NF-kB family transcription factors that act to form dimers and what are they encoded by?
p50, p52, p65 (RelA0, c-Rel, RelB – encoded for by NFKB1, NFKB2, RELA, REL, and RELB genes
What can contribute to activation/inhibition of NF-kB proteins?
Post-translational modifications like phosphorylation and acetylation
What helps form the NF-kB dimers and where do they bind?
Rho homology domain - RHD help with formation and they bind at kappaB sites - kB sites have variable sequences for different specificity of dimers to bind
What are the NF-kB families of transcription factors?
Class II - have TAD domain (trans activation domains) that are necessary for positive regulation of gene expression - Rels
Class I - no TAD only dimers p50 or p52 repress transcription
What are the NF-kB kinases?
IKK - alpha, beta and gamma=NEMO
What is required for signaling in canonical/classical NF-kB pathways?`
NEMO
Which proteins are phosphorylated during canonical and non-canonical pathways of NF-kB?
Canonical - IkBalpha, beta and epsilon
Non-canonical - p100
What activates canonical and non-canonical pathways of NF-kB?
Canonical - wide array of receptors, TLR, notch, EGFR, cytokine
Non-canonical - TNFR superfamily members
Explain the NF-kB non-canonical pathway?
IKKalpha is activated by NIK which phosphorylates IKKalpha which phosphorylates p100 to promotes p52 processing to dimerize with Relb to regulate gene in nucleus via kappaB sites
What are TLRs important for?
Innate immunity to recognize and binds pathogens/dying tissue - but also shape adaptive immune response
What are PAMPs and DAMPs?
PAMPs = pathogen associated molecular pattern - used as adjuvants to enhance adaptive immune response and DAMPs = damage associated molecular pattern (aka bugs) secreted by dying cells - both recognized and bound by TLRs
Which TLRs are extracellular and which are intracellular?
extra - TLR1, 2, 4, 5, 6
intra - TLR3, 7, 8, 9 (endocytic)
Which TLRs form dimers with eachother?
2 and 1
2 and 6
What are PPRs?
Pattern recognition receptors - TLRs are an example as well as NLR (nucleotide binding oligomerization domain like recpetors) and RLR (retinoic acid-induible gene-I like receptors)
Where are TLRs expressed?
Immune cells like T and B, DC, macrophage but also in fibroblasts and epithelial
What do TLRs use to signal?
MYD88 except for TLR3 which uses TRIF or TLR4 which can use TRIF or MYD88
What type of bacteria do TLRs recognize?
Different TLRs recognize different PAMPs from different microbes - real responses usually involve many TLRs due to many types of microbes
What pathways do TLRs activate?
NF-kB, MAPKinase, IRF (interferon response factors), AKT
What else does TLR4 signaling use besides TRIF or MYD88?
LPS binds to LPS binding protein (LBP) in the blood which carries it to CD14 a coreceptor on the cell surface and MD2 an accessory protein
What does hypoxia use to induce signaling?
HIF family of transcription factors with HIF-1alpha being the major, 2alpha and 3alpha pair as hetodimer with HIF-1beta where dimer goes to nucleus to initiate transcription by bindingHRE - hypoxia response element
How do NF-kB and HIF interact?
NF-kB can stimulate HIF-1alpha levels but under hypoxia HIF-1alpha and HIF-1beta can also stimulate NF-kB which promotes inflammation
Is HIFalpha/beta inhibiting or promoting inflammation?
It can do either, normal conditions anti-inflammatory, under hypoxia proinflammatory
