Viral interaction with host cell sumoylation system

Viral Interaction with Host cell SUMOylation system

R. SANTHAMANIR. SANTHAMANI I. SOPHIAI. SOPHIA

Ph.D. StudentPh.D. StudentDivision of VirologyDivision of Virology

Indian Veterinary Research InstituteIndian Veterinary Research InstituteMukteswarMukteswar

Uttarakhand.Uttarakhand.

Contents

1. What is sumoylation?

2. Discovery

3. Sumoylation pathway

4. Importance of sumoylation

5. Immunity and sumoylation

6. Viruses and sumoylation

7. What we gain?

05/08/14 Viruses and SUMOylation 2

.

Phosphorylation

Glycosylation

Ubiquitinatination

05/08/14 Viruses and SUMOylation

What is sumoylation?

SUMO – Small Ubiquitin like Modifier

101 amino acid length

Post translational modification

Location: nucleus - eukaryotes

3(Saitoh et al., 1997)

DISCOVERY

Discovered independently Study of Pro-Pro and Pro-NA interactions - Yeast 2-hybrid screens (Boddy et al., 1996; Okura et al., 1996; Shen et al., 1996) Biochemical analysis of nuclear transport component, RanGAP1 (Matunis et al., 1996; Mahajan et al., 1997) cDNA mapping of human chromosome 21 (Lapenta et al., 1997)known by

UBL1 (Shen et al., 1996)

Sentrin (Kamitani et al., 1997)

GMP1 (Matunis et al., 1996)

hSMT3C (Lapenta etal., 1997)


known to be proteins involved in Sumoylation - SUMO proteins

4

Sumoylation pathway

Between lysine residue of substrate and C- terminal GG motif of SUMO

Consensus motif Ψ-K-x-D/E

Between lysine residue of substrate and C- terminal GG motif of SUMO

Consensus motif Ψ-K-x-D/E Sumoylated

protein(Desterro et al., 1997)05/08/14 Viruses and SUMOylation 5

Why Sumoylation system is needed??

Sumolytion of vital cell

proteins pRB, PML and

RepA protein

Targeted transport

between nucleus and

cytoplasm

Gives stability to many

labile proteins – highly

folded structure

(Bayer et al., 1998)



Immunity and sumoylation…

7

Sumoylation of RIG 1, MDA 5 and Pellino 1

Upregulation of IFN production

Represses viral replication

Sumoylation of RIG 1, MDA 5 and Pellino 1

Upregulation of IFN production

Represses viral replication


Immunity and sumoylation …

(Zeng et al., 2010 & Wilson et al., 2012)

Innate immunity

8


TLR PATHWAY

9


(Kim et al., 2011)

RLR PATHWAY

(Zeng et al., 2010)Sumoylation of RIG 1 and MDA 5



Type I IFN

Genetically encoded proteins - target the invading viruses

Expressed at a constant level

Allows the viral infection to be halted quickly

Genetically encoded proteins - target the invading viruses

Expressed at a constant level

Allows the viral infection to be halted quickly


Immunity and sumoylation …

Intrinsic immunity

11

(Everett et al., 2009)

Members of TRIM family of

proteins

Sumoylation of TRIM family proteins play

a role in antiviral activity

TRIM5α – retrovirus infections

TRIM5α has SIM motif to bind

with sumoylated CA of MLV


(Nakayama et al., 2012)

Intrinsic immunity

12


05/08/14Viruses and SUMOylation

(Geoffroy et al., 2011)

PML protein – Antiviral activity

13


Eg. HSV


Viruses and Sumoylation

Sumoylation process is exploited by viral pathogen to regulate their

activity

Many of the DNA viruses use sumoylation for targeting their vital

proteins to the nucleus to exploit host cell nuclear machinery

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Virus Protein Function References

Adenovirus E1B-55K Transformation Endter et al., 2001

Adeno-associated virus Rep 78 Latency Weger et al., 2004

Epstein-Barr virus Rta (FRLF1)EBNA3C

Lytic activationTranscription

Chang et al., 2004Rosendorff et al., 2004

Moloney murine leukemia virus

CA Early stage of infection Yeuh et al., 2006

Human T cell leukemia virus

Tax Induction of cancer Lamsoul et al., 2005

Papillomavirus E1E2

ReplicationTranscription of oncogenes E6 , E7

Rangasamy et al., 2000

Marusic et al., 2010

Parainfluenza virus 5 P Replication Sun et al., 2011


Sumoylation of viral proteins

15

Viruses and sumoylation…


Viruses have evolved to exploit further this intricate mechanism for

their own benefit

vProteins

Mimic sumoylation enzymes

Act as STUbLs

Targets sumoylation enzymes

Modulate sumoylation of specific host SUMO

substrates

Can viruses exploit more …? If so…Can viruses exploit more …? If so…how??? how???

16

(Chang et al., 2010)


05/08/14Viral interaction with host cell sumoylation

system

vProteins that mimic sumoylation enzymes

KSHV – KbZIP

Binds with SUMO

Sumoylate the binding partners - p53 & pRB

SIM motifSIM

motif

SUMO ligase

(Pennella et al., 2010)


Favourable for virus?


system

vProteins that act as STUbLs

HSV – ICP0 protein

Bind to sumoylated PML

Ubiquitination and proteasomal degradation of PML

Act as Ubiquitin

ligase

SIM like

motif

SIM like

motif

(Perry et al., 2008)



system

vProteins that targets sumoylation enzymes

Adenovirus Adenovirus

Sumoylation reducedEg. PML

(Boggio et al., 2004)



system

HPV L2HPV E6

Viral cycle (Heaton et al., 2011)

Sumo ligase

Sumoylating pRB

Maintains cell in quiescent

Ebola virus VP35

Sumoylation of IRF7

Transcriptin of IFN reduced

(Chang et al., 2009)



system

vProteins that modulate vProteins that modulate sumoylation of specific host sumoylation of specific host

SUMO substratesSUMO substrates

Adenovirus E1A, Papilloma virus E7

pRB

Maintains cell at definite stage of cell cycle

Cell enters S-Phase *favourable for virus replication

E2F

(Ledl et al., 2005)



system

p53 - remains in nucleus

Cell cycle arrest, apoptotic signalling in viral infected cells

Adenovirus E1B

Sumoylates p53 &targets it to cytoplasm, makes it non-functional

Contd…

Sumo ligaseSumo ligase

(Lazo et al., 2011)


(Wilson, 2012)05/08/14 Viruses and SUMOylation

Viruses and sumoylation : sumoylation : In total!! In total!!


What we gain??..

Better understanding of

Current knowledge on virus cell interaction

Nuclear targeting system

Signalling systems are regulated by sumoylation

Cellular regulatory functions

Some aspects of pathogenesis of Cancer

24


Only Only knowledge??..knowledge??..

SUMO gene fusion technology for expressing labile proteins like granzyme

If attaching SUMO to the N-terminus of poorly expressed proteins dramatically enhances the level of expression (Butt et al., 2005)

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Sumoylation is an essential PTM system in eukaryotes

Plays vital role in PTM of critical protein involved in overall cell signalling

systems including signalling pathways of intrinsic and innate immunity

Vital for transport of proteins between cytosol and nucleus

There are established intricate connections between sumoylation, viral

infection and cancer pathogenesis

SUMO fusion technology is a promising technique for bulk expression of

difficult to express proteins

May be having important role in prion pathogenesis but needs to be

investigated

To conclude…To conclude…


Future….????Future….????

Role of Sumoylation in prion diseases? For bulk production of recombinant antibodies ?

Targeted delivery to nucleus by sumoylation?

Drugs/chemicals/therapeutics with property of

controlled regulation of sumoylation for treating

cancer and viral infections?

27

THANK YOU


Viral interaction with host cell sumoylation system

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