ERAP zero.pptx

ENDOPLASMIC RETICULUM
AMINOPEPTIDASE (ERAP)
In Rheumatologic Diseases
Here is where your presentation begins
SMF Ilmu Penyakit Dalam FK Unair-RSUD Dr. Soetomo
Surabaya
Oleh
Iyzzul Milady
Pembimbing
Dr. dr. Yuliasih, Sp.PD, K-R, FINASIM

INTRODUCTION
chronic activation of innate and
adaptive immune system components
Endoplasmic reticulum aminopeptidase 1
(ERAP1) and 2 (ERAP2)
Autoimmune and autoinflammatory diseases affect various organ systems in the body
Abnormally enhanced
proinflammatory immune responses
tissue inflammation and damage
Cleave HLA class I-binding peptides, defining
the peptide repertoire presented for immune
recognition
Associated with genome-wide significance
with rheumatic diseases
• ankylosing spondylitis (AS)
• Psoriasis
• Behçet's disease (BD)
Has been identified as being one of important
immune genes to play a role in autoimmunity
Aldhamen, Y. A. and Rastall, D. P. W. (2016) ‘Immunity Autoimmune Disease-Associated Variants of Extracellular Endoplasmic Reticulum Aminopeptidase 1 Induce Altered Innate Immune Responses by Human
Immune Cells’, J Innate Immun, 48823, pp. 275–289. doi: 10.1159/000368899.
Ombrello, M. J. et al. (2016) ‘Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics’, Curr Opin Rheumatol, 27(4), pp. 349–356. doi: 10.1097/BOR.0000000000000189.Endoplasmic.
Zhang, Z. et al. (2017) ‘Brief Report: Functional Interaction of Endoplasmic Reticulum Aminopeptidase 2 and HLA–B27 Activates the Unfolded Protein Response’, Arthritis and Rheumatology, 69

ERAP DEFINITION
Additional processing of peptides necessary to
increase and to refine the variety available for
binding to Major Histocompatibility Complex
(MHC)/Human Leukocyte Antigen (HLA) class I
molecules
Endoplasmic Reticulum Aminopeptidase (ERAP)1 and ERAP2
zinc-metallopeptidases of the oxytocinase M1 subfamily
ERAP enzymes trim amino acid residues from
the NH2 terminus of polypeptides to generate
the optimal length antigenic peptides for
loading onto HLA class I molecules
peptides transported to the ER by TAP
Tran, T. M. et al. (2016) ‘Endoplasmic reticulum aminopeptidase 1 and rheumatic disease: functional variation’, Curr Opin Rheumatol, 27(4), pp. 357–363.
Lee, E. D. (2017) ‘Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance?’, Placenta, 176(3), pp. 139–148.
Maben, Z. et al. (2021) ‘Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1’, J Med Chem, 63(1), pp. 103–121. doi: 10.1021/acs.jmedchem.9b00293.Discovery.

ERAP STRUCTURE
Figure 1. Schematic diagram of ERAP1
The locations of common (>5% frequency) naturally
occurring amino acid variants and their corresponding
SNPs are shown. The rheumatic disease-associated
variants (127, 349, 528, 575, 725, and 730) are
ERAP1 has four protein domains, with domain II having catalytic activity and carrying the
GAMEN and Zn-binding HExxHx18E motifs
Figure 2. Rheumatic disease-associated missense variants
of ERAP1. A surface map of ERAP1 demonstrates the locations
of six rheumatic disease-associated amino acid substitutions of
ERAP1 (shown as red spheres). The surface coloring indicates
the domain structures (I = blue, II = green, III = orange, IV =
purple) and identifies the enzyme’s catalytic site (pink), which
contains the catalytic Zn2+ molecule (black sphere).
Tran, T. M. et al. (2016) ‘Endoplasmic reticulum aminopeptidase 1 and rheumatic disease: functional
variation’, Curr Opin Rheumatol, 27(4), pp. 357–363. doi: 10.1097/BOR.0000000000000188.Endoplasmic.

ERAP TRIM
To fit in the groove in most MHC class I
molecules, antigenic peptides must have a
length of 8–10 residues
recognized by circulating cytotoxic T
lymphocytes
non- native peptides (e.g., from viral proteins)
are presented
Fig. 5. Proposed model based on present observations to explain the substrate preference of ERAP1 (molecular ruler). (A) High-affinity
binding of optimal substrates through the C-terminal hydrophobic residue and active site. (B) Release of antigenic products (eight to
nine residues) after removal of additional N-terminal residues. Affinity is low because it is unable to reach to the active site. (C) Poor
substrates (fewer than nine residues) havelow affinity because they can interact only with the active site, or if they bind to the
hydrophobic pocket, their N-terminal residues cannot reach the active site. (D) A poor substrate has low affinity because its C-terminal
residue has a charged side chain
Chang, S. C. et al. (2005) ‘The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism’, Proceedings of the National Academy of Sciences of the
United States of America, 102(47), pp. 17107–17112. doi: 10.1073/pnas.0500721102.

ERAP FUNCTION
ERAP1 and ERAP2 enzymes play an important role in the biological processes requiring
trimming of amino acid residues at the N-terminus of polypeptides.
ERAP1
• cleaves hydrophobic
amino acid residues,
except proline, and
peptides with a
hydrophobic C-terminus
ERAP2
• hydrolyzes the basic
residues Arg and Lys.
Alvarez-Navarro, C. and López de Castro, J. A. (2014) ‘ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases’, Molecular Immunology, 57(1), pp. 12–21.
Tsujimoto, M. et al. (2020) ‘Endoplasmic reticulum aminopeptidase 1 beyond antigenic peptide-processing enzyme in the endoplasmic reticulum’, Biological and Pharmaceutical Bulletin, 43(2), pp. 207–214. doi:
10.1248/bpb.b19-00857.

ERAP FUNCTION : Regulation of blood
pressure, hypertension and angiogenesis
Impairment of ERAP1
expression inhibited the
proliferation
• migration and network
formation of endothelial cells in
vitro and angiogenesis in vivo
• these effects could be mediated
by ERAP1 involvement in the
activation of endothelial
integrins
in vitro studies
ERAP inactivates
angiotensin II through
its conversion to the
inactive angiotensin IV
and also converts
kallidin to bradykinin
case control study
● association of the natural
K528R polymorphism of the
enzyme with hypertension
● ↓hydrolytic activity toward
angiotensin II and kallidin
could be related to the
capacity of ERAP1 variants to
process peptide hormones
involved in the regulation of
blood pressure

ERAP FUNCTION : Innate Immunity
NK cells from the ERAP1−/− mice exhibit increased
activation in response to innate immune stimuli
• stimulation of splenocytes from ERAP1−/−− mice re-sulted in
increased levels of NK activation markers and proinflammatory
cytokine secretion including TNF-α, IL-6, and IL-1β, all of which are
also implicated in autoinflammation and autoimmunity
ERAP1 has also been shown to have a direct role in innate immunity and may contribute to
autoinflammatory and auto-immune diseases via additional functions
ERAP1 is involved in proteolytic cleaving of several cytokine
receptors, in-cluding TNF-R1, IL-6Rα and type II IL-1 decoy receptor
(IL-1RII)
Pepelyayeva, Y. and Amal, A. (2019) ‘Human Immunology The role of ERAP1 in autoinflammation and autoimmunity’, 80(January), pp. 302–309. doi: 10.1016/j.humimm.2019.02.013.

ERAP FUNCTION : ANTIGEN PRESENTATION
The lack or downregulation of ERAP1 expression upsets the antigen-presenting
properties and immunological function of MHC-I molecules in the host defense
against infection
demonstrated by altered immunodominance,
epitope processing and T-cell responses against
Toxoplasma gondii, lymphocytic choriomeningitis virus,
and cytomegalovirus
viruses evolved escape mechanisms targeting ERAP1
and post- proteasomal processing by mutating N-
terminal flanking residues of immunodominant viral
epitopes, as observed in HIV.
ERAPs seem to play a role also in thymic selection by affecting the
immunopeptidome of antigen-presenting cells in the thymus
• CD8+ cytotoxic T lymphocytes, expressing clonally different T cell receptors (TCR) are selected and mature in
the thymus
• ERAP2 haplotype associated with the highest ERAP2 expression contained all risk alleles for autoimmune
diseases and malignancies
Chang, S. C. et al. (2005) ‘The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism’, Proceedings of the National Academy of Sciences of the United
States of America, 102(47), pp. 17107–17112. doi: 10.1073/pnas.0500721102.

ERAP FUNCTION : ANTIGEN PRESENTATION
Endogenous and exogenous
antigen presentation
pathways showing the
involvement of CD8+ and
CD4+ T cells, respectively.
Aminopeptidase 1 (ERAP1) is
involved in the processing of
endogenous peptides; on the
other hand, cathepsins S, L,
B, and D and asparaginyl
cysteine endoprotease are
involved in the processing of
exogenous peptides
Chakraborti, S. and Dhalla, N. S. (2017) Pathophysiological Aspects of Proteases, Pathophysiological Aspects of Proteases. doi: 10.1007/978-981-10-6141-7

• Ankylosing Spondylitis (AS)
• Psoriasis
• Behçet’s disease
• Other autoimmune diseases
The Role of ERAP in
Rheumatologic Disease

affects an estimated 0.9–
1.4% of the adult
population in the U.S.
Ankylosing Spondylitis (AS)
Heritable chronic autoinflammatory disease affecting the axial skeleton
primarily affects the spine and the
sacroiliac (SI) joints, with sacroiliitis
being its hallmark feature
The progression
The age of onset of AS
symptoms: teen to early
twenties
the diagnosis of AS is delayed by 8–10 years due to its
gradual progression and ambiguous presentation joint fusion
syndesmophyte formation between
adjacent vertebra
excessive osteoproliferation
Gül, A. (2019) ‘Textbook of Autoinflammation’, Textbook of Autoinflammation. doi: 10.1007/978-3-319-98605-0
Pedersen, S. J. and Maksymowych, W. P. (2019) ‘The Pathogenesis of Ankylosing Spondylitis: an Update’, Current Rheumatology Reports, 21(10). doi: 10.1007/s11926-019-0856-3.

AS is known: 20.4% is
considered associated with
HLA-B*27 and only 7.4%
with non-HLA-B*27 genes.
The first non-MHC genes
clearly associated with AS
were ERAP-1, ERAP-2, and
LNPEP (leucyl/cysteinyl
aminopeptidase)
The role of ERAP in Ankylosing Spondylitis
The ERAP-1 allele variant rs30187 is only associated with AS in the presence of HLA-B*27 or HLA-
B*40
In the ERAP-1 molecule, the amino acid variant of rs30187 is located at the enzymatically active site,
which may therefore alter its function
This SNP has been associated with decreased trimming of peptides in vitro (a 40% reduction)
The disease-associated ERAP-1 SNP rs10050860 has been shown to be functionally silent
(Gül, 2019; Pedersen and Maksymowych, 2019)

Schematic of proposed pathological roles of HLA-B*27 and
associated molecules during antigen processing and
presentation in the pathogenesis of ankylosing spondylitis
• Target proteins are initially degraded into peptide
fragments in length by the proteasome. Antigen
peptides then enter the endoplasmic reticulum (ER)
through transporter associated with antigen
processing (TAP). N-terminal extended precursors are
trimmed by ERAP1 and ERAP2 into shorter
oligopeptides (8- to 10-mers),
• The peptides subsequently enter the Golgi apparatus
for generation of mature epitopes
• The complex ofHLA-B*27-β2m-peptide is transported
via coat protein complex II (COPII) vesicles. COPII
vesicles are formed at a ribosome- free ER exit site,
and protein transport protein SEC16A regulates this
process
• Due to altered function of ERAP1 and ERAP2, various
longer peptides may bind to HLA-B*27 and form an
arthritogenic complex which can stimulate immune
response via CD8+ T cell activation
• The complex may also enhance the formation of HLA-
B*27 open conformations via endocytic recycling.
Misfolding proteins trigger ER stress and can amplify
unfolded protein response (UPR) and autophagy
Nakamura, A., Boroojeni, S. F. and Haroon, N. (2021) ‘Aberrant antigen processing and presentation: Key pathogenic
factors leading to immune activation in Ankylosing spondylitis’, Seminars in Immunopathology, 43(2), pp. 245–253.

Haplotypes of common ERAP1 missense
variants in HapMap populations
Haplotypes were determined in 80
unrelated members of CEU
population and 80 unrelated
members of the ASN population.
Haplotypes with frequencies > 1% in
either CEU or ASN population are
displayed. Genotypes for rs72773968
(T12I) were not present in the
HapMap data. Non-ancestral AAs are
shown as grey shaded boxes. AA,
amino acid (single letter code); CEU,
CEPH, Utah residents with ancestry
from northern and western Europe;
ASN, east Asian, the combined
Japanese in Tokyo (JPT) and Han
Chinese in Beijing (CHB)
Ombrello, M. J. et al. (2016) ‘Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics’, Curr Opin Rheumatol, 27(4), pp. 349–356. doi: 10.1097/BOR.0000000000000189

Summary of ERAP1 haplotype associations in ankylosing
spondylitis and comparison to ERAP1 allotypes
from HapMap CEU and ASN populations

develop due to over-proliferation of
keratinocytes in response to inflammatory
infiltration and damage mediated by
• innate immune cells (macrophages and DCs),
• adaptive immune cells (T cells)
• proinflammatory cytokines (TNFα)
Several genes involved in theflammasome
pathway have been shown to be associated
with psoriasis
• rs10733113 polymorphism in NLRP3
• rs2043211 polymorphism in CARD8
The role of ERAP in Psoriasis
Psoriasis is a chronic autoimmune disease of the skin, characterized by scaly plaque formation, and
is associated with psoriatic arthritis, affects an estimated 2–3% of the population

The role of ERAP in Psoriasis
Psoriasis has a strong
association with HLA-
Cw6, and interestingly, a
strong association with
ERAP1 in HLA-Cw6
positive individuals
ERAP1 rs27525 SNP and
another GWAS in Han
Chinese population
reported the ERAP1
rs151823 variant to be
associated with psoriasis
ERAP1’s role in antigen
presentation serves as the
underlying mechanism for its
role in the pathogenesis of
psoriasis, where specific ERAP1
variants influence the peptide
immunodominance in a manner
where autoreactive CTLs
infiltrate the psoriatic lesions.
Genome-wide association
studies implicated ERAP1
(rs27524/rs30187) only in the
C*06:02 positive disease
Ombrello, M. J. et al. (2016) ‘Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics’, Curr Opin Rheumatol, 27(4), pp. 349–356. doi: 10.1097/BOR.0000000000000189.

It is strongly associated with HLA- B*51 and less strongly with
HLA-A*26, HLA-B*15, HLA-B*57 and HLA-B*27
Meanwhile, the presence of the HLA-A*03 and HLA-B*49
variants have been shown to be protective.
Two ERAP1 SNPs have been found to be associated with
Behcet’s, namely rs17482078 and rs10050860
there is an epistatic effect between ERAP1 rs17482078 and
HLA-B*57
The role of ERAP in Behçet’s disease
multisystemic autoinflammatory disease on unknown etiology which presents with
oral/genital ulcers, systemic vasculitis, ocular, gastrointestinal and skin inflammation, with
an age of onset at 30–40 years of age
Gül, A. (2019) ‘Textbook of Autoinflammation’, Textbook of Autoinflammation. doi: 10.1007/978-3-319-98605-0
Leccese, P. and Alpsoy, E. (2019) ‘Behçet’s disease: An overview of etiopathogenesis’, Frontiers in Immunology, 10(MAY). doi: 10.3389/fimmu.2019.01067.
Pepelyayeva, Y. and Amal, A. (2019) ‘Human Immunology The role of ERAP1 in autoin fl ammation and autoimmunity’, 80(January), pp. 302–309. doi: 10.1016/j.humimm.2019.02.013.

The role of ERAP in Behçet’s disease
The same SNPs associated to BD risk resulted protective against AS and psoriasis:
this effect, however depends on the different HLA interacting with ERAP1
ERAP1 rs17482078 (p.Arg725Gln) might influence the peptide repertoire binding to
HLA-B∗51
T-cell and natural killer (NK) cell recognition were probably affected, providing the
basis for the association of ERAP1 and HLA-B∗51 with BD
A very recent alternative pathogenic hypothesis linking HLA-B∗51 with BD involves
the gut microbiome and the HLA-B∗51 misfolding
Salmaninejad, A. et al. (2019) ‘Behçet’s disease: An immunogenetic perspective’, Journal of Cellular Physiology, 234(6), pp. 8055–8074. doi: 10.1002/jcp.27576.

very rare form (almost 1–5
cases/500000) of the ocular-
specific inflammatory disorder
which is unique among
autoimmunity diseases
The role of ERAP in Birdshot chorioretinopathy
(BCSR)
significant association
between the ERAP2
rs10044354 SNP and
risk of BSCR
the precise role of the
HLA-A29 in BSCR
immunopathogenesis
remains slightly
comprehended.
strong association
with HLA-A29:02 allele
Babaie, F. et al. (2020) ‘The roles of ERAP1 and ERAP2 in autoimmunity and cancer immunity : New insights and perspective’, 121(December 2019), pp. 7–19. doi: 10.1016/j.molimm.2020.02.020

The role of ERAP in Inflammatory bowel disease
immune dysregulation
of the innate immune
response to the gut
microbiota
Two main forms
• Ulcerative colitis (UC)
• Crohn's diseases (CD)
The ERAP1 SNP, rs30187, has been
shown to be associated with Crohn’s
disease
• Turkish cohort: ERAP1 variant
rs26653 was associated with IBD
• Spanish Cohort association
between the HLA-C*07 allele and
ERAP1 SNP rs30187 in IBD
• 5–10% of Ankylosing
Spondylitis patients also have
inflammatory bowel disease
• up to 46% of patients with
spondyloarthritis have
microscopic gut inflammation

The role of ERAP in Insulin dependent
diabetes mellitus (IDDM)
IDDM is a polygenic autoimmune disease, which involves the destruction of insulin-
producing β-pancreatic cells, resulting in insulin deficiency and hyperglycemia
The major genes associated with IDDM are MHC class II genes HLA-DQB1 and
HLA-DRB1
HLA class I gene polymorphisms have also been found to be associated with
increased risk of developing IDDM, namely HLA-A*24:02 and HLA- B*39:06
the rs30187 SNP in the ERAP1 gene was found to also be associated with IDDM
it may be that ERAP1 contributes to the pathogenesis of IDDM via its aminopeptidase
function by altering the immunopeptidome, affecting whether pre-proinsulin peptides are
recognized by the CTLs and trigger β-cell killing

The role of ERAP in Multiple Sclerosis
Autoimmune disease affecting
the central nervous System
• demyelination of the nerves
occur with the involvement of
both T and B cells,
• causing motor defects,
hemiparesis, visual deficits,
ataxia and cognitive
impairments
The rs30187 ERAP1 variant has been
shown to be associated with MS
• addition of the rs30187 ERAP1
variant to PBMCs in-vitro enhanced
IL-1β, TNF-α, and IL-6 secretion and
activation of NK, DCs, and T cells in
caspase-1 dependent manner
it is also plausible that ERAP1’s involvement in the pathogenesis of MS is via our recently
identified potential role for ERAP1 in Tr1 cell biology
• “Tr1-like” cells from MS patients have been shown to produce reduced levels of IL-10
compared to healthy patients

Summary
Endoplasmic Reticulum Aminopeptidase
ERAP1 and ERAP2 function to cleave HLA class I
binding peptides, determining the peptide repertoire
presented for immune recognition
ERAP has an important role in the regulation of adaptive
(HLA Class I) immunity, innate immunity through
proteolytic cleavage of several cytokine receptors, and
regulation of blood pressure
Several variants of the ERAP coding are associated with
rheumatic diseases, such as ankylosing spondylitis (AS),
psoriasis, and Behçet's disease (BD), and other disease
of which have strong associations with MHC Class I
molecules

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