NLRP3 NOD and HOIL defects

Question 1

What 3 domains do NOD-like proteins have?

Answer 1

Ligand binding domain (normally LRRs)

NOD (oligomerisation) domain

Effector binding domain (PYD for NLRP) (CARD for NOD proteins).

Question 2

What does the ligand recognition domains of NLRs bind to?

Answer 2

danger signals or PAMPs,

Question 3

what are the best NLRPs (cryopyrins)?

Answer 3

NLRP1 and 3 which have inflammasome complexes.

PYD ASC (adaptor protein) and CARD which recruits caspase 1 to cleave and activate IL-1B.

Question 4

What does CAPS stand for and what three diseases are there?

Answer 4

cyropyrin associated periodic syndroms CAPS

Familal cold antiinflammatory syndrome FCAS
Mukle wells syndrome MWS
CINCA

Question 5

Which out of FCAS, MWS and CINCA are the most severe?

Answer 5

FCAS least severe, CINCA most severe.

Question 6

Are the CAPS, FCAS, MWS or CINCA AR/AD or de novo mutations?

Are they loss or GOF mutations of NLRP3?

Answer 6

FCAS and MWS are AD mostly and CINCA is d novo mutations.

They are GOF mutations of NLRP3 (affecting NOD domain e.g. to increase oligomerization)

Question 7

What are the common symptoms and complications of these CAPS?

Answer 7

recurrent fever, chills, urticaria and joint pain.

Complications can by amyloidosis and neurological disorders.

Question 8

Do NOD proteins create inflammasomes?

Answer 8

No, they are more like TLRs, they activate NF-kB.

Question 9

What are the specific ligands for NOD1 and NOD2?

Answer 9

NOD1 ligand is LPS
NOD2 ligand is muramyl dipeptide (MDP)
Both are components of bacterial cell walls.

Question 10

What autophagosome protein do NOD1 and 2 interact with?

Answer 10

ATG16L1

Interaction with activated NOD1/2 stimulates autophagosome formation around pathogen.

Question 11

What LOF mutation in NODs leads to Crohn’s like presentation? And why?

Answer 11

NOD2 LOF due to polymorphisms affecting ligand recognition.

Or frameshift mutation and premature stop codon formation.

Inability to stimulate NF-KB through this pathway.

Pathogens in the gut may not be controlled locally.

Question 12

How does hetero/homozygosity of NOD2 LOF mutations affect risk of Crohn’s?
What other mutations have been linked to Crohn’s disease?

Answer 12

heterozygous- 2-4 fold increase in risk.
homozygous, 20-40 fold increase in risk of crohn’s
Mutations in ATG16L1.

Question 13

What missense mutations can lead to Blau syndrome (autoinflammatory condition)?

Answer 13

NOD2 mutations which are GOF of the NOD domains.

INcreased NF-kB activation -granulomatous arthritis uveitis skin rashes.

Question 14

What condition is associated with an autoinflammatory and immunodeficiency presentation?

Answer 14

HOIL-1 deficiency (part of LUBAC complex with SHARPIN and HOIP).

Question 15

What does LUBAC do? What is amylopetinosis?

Answer 15

LUBAC is important for ubiquitination.

deposition of glycoproteins.

Question 16

What target does LUBAC affect for regulation of NF-kB?

Answer 16

LUBAC will ubiquitinate NEMO to enable its activation of NF-KB.
HOIL-1 deficiency, NEMO not U or activated- no NF-KB and immunodeficiency.

Question 17

What target does LUBAC affect for regulation of inflammasome?

Answer 17

LUBAC ubquitination important for negative regulation of caspase-1.
HOIL-1 deficiency, then overactivatnio of caspase 1 and IL-1B autoinflammation.