Lecture 15: Immune System Protein Trafficking + viruses Flashcards by Tami Ojewole

MHC stands for ___

Major Histocompatibility Complex

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MHC are ____ on ___

Oligomeric protein complexes on the cell surface

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MHC is ___ meaning that it has multiple alleles

polymorphic

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MHC binds to ____ (___ amino acids)

wide variety of peptide antigens (8-24 a.a)

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MHC (general) presents antigens to ____

T-cells

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antigens to MHC I cause ___ while antigens to MHC II cause ___

cell death
T-cell stimulation

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MHC complexes rich the cell surface with ___ using ____

bound peptide antigens
different trafficking pathways

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class MHC I description

a-chain (transmembrane heavy chain)-polymorphic
->a1 +a2 =peptide binding groove
b-microglobulin - non polymorphic/ soluble

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class MHC II description

a-chain + b-chain (transmembrane region)- 2 chains
a1 +b1 =peptide binding groove (polymorphic)

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MHC I is present only in ___

nucleated cells (not in blood cells) in vertebrates

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MHC II is present only in ____

antigens presenting cells (ex. dendritic cells, b-cells, macrophages)

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MHC I presents antigen to ___

cytotoxic T-cells

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MHC II presents antigen to ___

helper + regulatory T-cells

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source of peptide antigen (MHC I)

-proteins made in cytoplasm

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source of peptide antigen (MHC II)

endocytosis PM + extracellular proteins

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If antigen on MHC I is foreign then ____

the cell is targeted for destruction

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receptor on cytotoxic T-cell that recognizes MHC I

CD8

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general structure of MHC I

heterodimer

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a-chain of MHC is ____ membrane protein

Type-1

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complete assembly of MHC I occurs in ___

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a-chain of MHC I associate with __, __, ___ before/during assembly in ____

calnexin*, calreticulin and ERp57
ER lumen

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a-chain of MHC I associate with B-microglobulin
when?

-shortly after synthesis (2 min)

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peptide binding groove of MHC I protein faces ___

lumen of ER

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antigens (peptides) for MHC I are transported from ____ into ____ by ____

*cytosol into ER lumen by TAP

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TAP is a ____ in ER membrane, ____-ase, & ____

Transporter ATP-ase heterodimer (TAP-1,TAP-2)

transport of antigens for MHC I into ER lumen is a ___-dependent process

ATP

peptides for MHC I (viral) are derived from ____

proteolysis of newly synthesized viral proteins in cytosol by Proteasome

Tapasin (Tsn) is an _____associated with

ER membrane glycoprotein TAP

Function of Tapasin

Facilitates peptide loading onto MHC I

___ motif on Tsn retains unloaded MHC I in ER

Tsn has a ____(ER-retention) motif

dilysine

TAP has a ____(NBD) for __ binding

nucleotide binding domain ATP

Tsn and fully loaded MHC I

Tsn releases MHC I to move to golgi and then cell surface

MHC I acts as a ___ for T-cell

a window

cytotoxic cell needs very little ___

cytoplasm (mostly nucleus)

In un-infected cells, most MHC I complexes are occupied by _____

peptides derived from cellular proteins (mostly defective proteins from ribosomes, some retirees)

In infected cells, most MHC I complexes are occupied by _____

viral peptides

state of MHC when cell is not fighting infection

-bound but with host proteins

receptor on helper T-cell that recognizes MHC II

CD4

MHC II a and B chain are both ___

type 1 membrane glycoproteins

peptide binding groove of MHC I binds peptides with ___ a.a

8-10

peptide binding groove of MHC II binds peptides with ___ a.a

12-20

assembly of MHC II begins in ____ and requires ___

ER chaperones

invariant chain facilitates transport of _____

MHC II complexes to endosomes

invariant chain prevents ___

binding of peptides to MHC II in ER (don't want MHC I peptides)

invariant chain is a ____

nonpolymorphic transmembrane protein(homotrimer)

invariant chain stimulates ___

exit of MHC II heterodimers from ER

invariant chain _____ peptide binding groove of MHC II by _____ in _____

is removed proteolysis endosomes

peptides of MHC II are derived from ___

degraded endocytosed material (bacteria, viruses) from cell surface

Proteasome _____ required to generate peptides for binding to MHC II

is not

After removal of invariant chain, MHC II binds to peptide in _____ which ____ complex

endosomes stabilizes

invariant chain contains ___ motif in ____

dileucine (LL/ML) cytoplasmic domain

Viral immune evasion strategies

-Avoiding antibodies-changing of surface proteins (flu,cold,coronaviruses) -Viral proteins that modulate host immune response

How do viral proteins modulate host immune response?

-Blocking expression of cytokines and prevention of programmed cell death (apoptosis) – Interfering with cellular immune response by disabling peptide presentation or impairing NK cell function

Viral Interference with MHC I Function (Post-Translational): generation of peptides

EBNA-1 protein contains Gly-Ala repeats which interferes with proteasome (no peptides degrades so no assembly on MHC I and export from ER)

Viral Interference with MHC I Function (Post-Translational): peptide transport in ER

-competes for peptide-binding of TAP -stabilizes TAP in conformation that it can't bind to ATP result: no peptides in ER, no assembly of MHC I, no export from ER

E3-19K is a ____

"immunosubversive” protein encoded by adenoviruses

adenoviruses are ___

small DNA viruses (often cause cold-like symptoms)

E3-19K has which motif?

KK motif in cytoplasm

E3-19K blocks the expression of ___ at _____ by preventing the ______

MHC I cell surface conversion of N-linked sugar into Endo H resistant forms

E3-19K binds to and retains MHC I in ___

E3-19K also binds to ___ and prevents binding to ____

TAP tapasin (peptide-loading)

CMV US3 and US10 have same function as ___ but don't prevent ___

E3-19K peptide loading

CMV US2 and US11 bind to ___ in___ and cause

MHC I ER dislocation

US11 localizes where?

in ER

proteasome inhibitor

ZL3VS

____inhibits US11-induced degradation of MHC (HC-heavy chain)

Blocking proteasome

US-11 leads to expression of ____

soluble, deglycosylated MHC I HC

Differential centrifugation refresher

-Start from cell homogenate -Spin at different speeds (g force) for various times -Obtain several fractions that are enriched in cell components (e.g. membranes) of various sizes

Differential centrifugation 1000 x g pellet

-whole cells, nuclei, cytoskeletons

Differential centrifugation 10,000 x g pellet

-mitochondria, lysosomes, peroxisomes

Differential centrifugation 100,000 x g pellet

microsomes, small vesicles

HIV Nef protein has multiple functions

* Not required for replication * Involved in immune deficiency

Nef protein operates ____

post ER/Golgi

Nef-induced degradation of ____ is blocked by inhibitors of ____

mature MHC-I acidic degradation

Lactacystine (Lact) inhibits____

proteasome

Bafilomycin (Baf A1) inhibits ___

proton pump in lysosomes

NH4Cl raises _____

pH of lysosomes

both bafilomycin +NH4Cl ___

disrupts function of lysosomes

HIV Nef causes _____

lysosomal-dependent degradation of MHC I (needs AP-1)

depletion of AP-1 effect on Nef-dependent degradation of MHC I

-inhibits degradation of MHC I(AP-1 moves MHC I from golgi to lysosomes)

______ interacts with AP-2 to accelerate endocytosis of CD4 and MHC-1, leading to ____

HIV-Nef selective removal of MHC I from surface of presenting cell

interference of MHC II mostly occurs in ___

endocytic pathway

Papilloma viruses + MHC II interference

produces E5 protein: replace subunit of proton pump -pH in endosomes/lysosomes increases -Proteolysis of endocytosed material is blocked -no peptide-loading of MHC II -decreased cell surface expression of MHC II

Lecture 15: Immune System Protein Trafficking + viruses Flashcards

(84 cards)