Putative SUMO-1 pathway
Sumoylation is a multi-step protein modification reaction. It implicates Small
ubiquitin-like modifier (SUMO) proteins, such as SMT3 suppressor of mif two 3 homolog 1
(SUMO-1). These proteins get attached covalently to lysine
residues of substrate/target proteins. As a result, in contrast to ubiquitination that
targets proteins for degradation, activities of the sumoylated proteins get modulated to
affect a number of biological functions, including control of gene expression,
maintenance of genome integrity, intracellular transport and protein stability , .
Attachment of SUMO-1 to substrate proteins is carried out
by enzymatic cascade involving SUMO-activating enzyme (E1), SUMO-conjugating enzyme (E2)
and SUMO protein ligase (E3). A group of proteases known as SENPs are involved in both
the maturation of SUMO precursors (endopeptidase cleavage) and deconjugation of the
targets (isopeptidase cleavage).
SUMO-1 is processed by SUMO1/sentrin specific peptidase 1
(SENP1) (endopeptidase cleavage) before being activated.
Processed SUMO-1, in the ATP-dependent manner, is covalently
linked to the SUMO E1-activating enzyme complex (SAE1/2)
composed of two catalytically active subunits, SUMO1 activating enzyme subunit 1
(SAE1) and Ubiquitin-like modifier activating enzyme 2
(SAE2). SUMO-1 is then
transferred to the SUMO E2-conjugating enzymes, such as Ubiquitin-conjugating enzyme E2I
(E2I) and Ubiquitin-conjugating enzyme E2E 3
(UBE2E3), that mediate target protein modification by SUMO
E3 ligases, such as RAN binding protein 2 (RanBP2),
Chromobox homolog 4 (Pc2) and specific E3-like ligases
PIAS1 and PIAS2 (Protein
inhibitors of activated STAT, 1 and 2) , , , , . Cleavage of the
SUMO-1 from the target protein is mediated by
SENP1 peptidase (isopeptidase cleavage) .
Mdm2 p53 binding protein homolog (MDM2) is an ubiquitin
ligase (E3) that acts on Tumor protein p53 (p53). It
attaches Ubiquitin to p53
leading to proteasomal degradation of the latter . E3 ligase
RanBP2 is a nuclear pore protein and E3 ligases
PIAS1 and PIAS2 are localized within the
nucleus. MDM2 is sumoylated during nuclear translocation by
RanBP2, and then sumoylated again in the nucleus by
PIAS1 and PIAS2 .
PIAS1 and PIAS2 also promote
sumoylation of several transcription factors, such as p53,
c-Jun and SP3. This
modification modulates their transcriptional activity, e.g.,
SUMO-1 modification silences
SP3 activity , .
Sumoylation is involved in both the direct regulation of
p53 protein stability and function via direct modification
of p53, and indirect modulation of the stability of
MDM2. Although, the functional consequence of direct
SUMO-1 modification of p53 is
under debate, it is generally believed that sumoylation represses activity of this
transcription factor. The indirect process has to do with, the turnover rate of
p53 being related to E3 ubiquitin ligase activity of
MDM2, the latter itself being a target of sumoylation.
SUMO-1-modified MDM2 cannot be
ubiquitinated as efficiently as the free MDM2. Thereby,
SUMO-1-modified MDM2 exhibits
reduced self-ubiquitination which leads to an accumulation of
MDM2. Since p53 is a target of
MDM2 E3 ubiquitin ligase activity, the
p53 levels stay low in the presence of
SUMO-1-modified MDM2 , .
RanBP2 promotes sumoylation of Ran GTPase activating
protein 1 (RanGAP1), stimulates
RanGAP1 functions and increases the accumulation of properly
folded RanGAP1 protein , , .
Activation of Nuclear factor NF-kappa-B (NF-kB) is
achieved by ubiquitination and proteasome-mediated degradation of inhibitory I-kappa-B
proteins (NFKBIA or NFKBIB). The latter inactivate
NF-kB by trapping it in the cytoplasm.
NFKBIA, conjugated to SUMO-1,
is resistant to ubiquitin-induced degradation. Thus, NFKBIA
sumoylation inhibits signal-induced activation of
NF-kB-dependent transcription .
The sumoylation of TNF receptor superfamily member 6
(FasR(CD95)), v-Myb myeloblastosis viral oncogene homolog
(c-Myb), Promyelocytic leukemia protein
(PML), Heat shock transcription factor 1
(HSF1), Heat shock transcription factor 2
(HSF2), Glucocorticoid receptor
(GCR-alpha), Nuclear antigen SP100
(SP100), Death-domain associated protein
(DAXX), and DNA topoisomerase II
(TOP2) regulates subcellular localization, stability and
functional activity of these proteins , , , , , , , , , , , , , , , , .
- Hay RT
SUMO-specific proteases: a twist in the tail.
Trends in cell biology 2007 Aug;17(8):370-6
- Tang Z, Hecker CM, Scheschonka A, Betz H
Protein interactions in the sumoylation cascade: lessons from X-ray structures.
The FEBS journal 2008 Jun;275(12):3003-15
- Desterro JM, Rodriguez MS, Kemp GD, Hay RT
Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1.
The Journal of biological chemistry 1999 Apr 9;274(15):10618-24
- Schmidt D, Muller S
Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity.
Proceedings of the National Academy of Sciences of the United States of America 2002 Mar 5;99(5):2872-7
- Okubo S, Hara F, Tsuchida Y, Shimotakahara S, Suzuki S, Hatanaka H, Yokoyama S, Tanaka H, Yasuda H, Shindo H
NMR structure of the N-terminal domain of SUMO ligase PIAS1 and its interaction with tumor suppressor p53 and A/T-rich DNA oligomers.
The Journal of biological chemistry 2004 Jul 23;279(30):31455-61
- Kim KI, Baek SH
SUMOylation code in cancer development and metastasis.
Molecules and cells 2006 Dec 31;22(3):247-53
- Kubbutat MH, Jones SN, Vousden KH
Regulation of p53 stability by Mdm2.
Nature 1997 May 15;387(6630):299-303
- Miyauchi Y, Yogosawa S, Honda R, Nishida T, Yasuda H
Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes.
The Journal of biological chemistry 2002 Dec 20;277(51):50131-6
- Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, Suske G
Transcription factor Sp3 is silenced through SUMO modification by PIAS1.
The EMBO journal 2002 Oct 1;21(19):5206-15
- Joseph J, Tan SH, Karpova TS, McNally JG, Dasso M
SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles.
The Journal of cell biology 2002 Feb 18;156(4):595-602
- Zhang H, Saitoh H, Matunis MJ
Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex.
Molecular and cellular biology 2002 Sep;22(18):6498-508
- Yi H, Friedman JL, Ferreira PA
The cyclophilin-like domain of Ran-binding protein-2 modulates selectively the activity of the ubiquitin-proteasome system and protein biogenesis.
The Journal of biological chemistry 2007 Nov 30;282(48):34770-8
- Desterro JM, Rodriguez MS, Hay RT
SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation.
Molecular cell 1998 Aug;2(2):233-9
- Tsytsykova AV, Tsitsikov EN, Wright DA, Futcher B, Geha RS
The mouse genome contains two expressed intronless retroposed pseudogenes for the sentrin/sumo-1/PIC1 conjugating enzyme Ubc9.
Molecular immunology 1998 Nov;35(16):1057-67
- Mao Y, Desai SD, Liu LF
SUMO-1 conjugation to human DNA topoisomerase II isozymes.
The Journal of biological chemistry 2000 Aug 25;275(34):26066-73
- Ryu SW, Chae SK, Kim E
Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9.
Biochemical and biophysical research communications 2000 Dec 9;279(1):6-10
- Goodson ML, Hong Y, Rogers R, Matunis MJ, Park-Sarge OK, Sarge KD
Sumo-1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor.
The Journal of biological chemistry 2001 May 25;276(21):18513-8
- Seeler JS, Marchio A, Losson R, Desterro JM, Hay RT, Chambon P, Dejean A
Common properties of nuclear body protein SP100 and TIF1alpha chromatin factor: role of SUMO modification.
Molecular and cellular biology 2001 May;21(10):3314-24
- Hong Y, Rogers R, Matunis MJ, Mayhew CN, Goodson ML, Park-Sarge OK, Sarge KD
Regulation of heat shock transcription factor 1 by stress-induced SUMO-1 modification.
The Journal of biological chemistry 2001 Oct 26;276(43):40263-7
- Bies J, Markus J, Wolff L
Covalent attachment of the SUMO-1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity.
The Journal of biological chemistry 2002 Mar 15;277(11):8999-9009
- Jang MS, Ryu SW, Kim E
Modification of Daxx by small ubiquitin-related modifier-1.
Biochemical and biophysical research communications 2002 Jul 12;295(2):495-500
- Le Drean Y, Mincheneau N, Le Goff P, Michel D
Potentiation of glucocorticoid receptor transcriptional activity by sumoylation.
Endocrinology 2002 Sep;143(9):3482-9
- Verger A, Perdomo J, Crossley M
Modification with SUMO. A role in transcriptional regulation.
EMBO reports 2003 Feb;4(2):137-42
- Hietakangas V, Ahlskog JK, Jakobsson AM, Hellesuo M, Sahlberg NM, Holmberg CI, Mikhailov A, Palvimo JJ, Pirkkala L, Sistonen L
Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1.
Molecular and cellular biology 2003 Apr;23(8):2953-68
- Isik S, Sano K, Tsutsui K, Seki M, Enomoto T, Saitoh H, Tsutsui K
The SUMO pathway is required for selective degradation of DNA topoisomerase IIbeta induced by a catalytic inhibitor ICRF-193(1).
FEBS letters 2003 Jul 10;546(2-3):374-8
- Anckar J, Hietakangas V, Denessiouk K, Thiele DJ, Johnson MS, Sistonen L
Inhibition of DNA binding by differential sumoylation of heat shock factors.
Molecular and cellular biology 2006 Feb;26(3):955-64
- Chen A, Wang PY, Yang YC, Huang YH, Yeh JJ, Chou YH, Cheng JT, Hong YR, Li SS
SUMO regulates the cytoplasmonuclear transport of its target protein Daxx.
Journal of cellular biochemistry 2006 Jul 1;98(4):895-911
- Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP
The mechanisms of PML-nuclear body formation.
Molecular cell 2006 Nov 3;24(3):331-9
- Meinecke I, Cinski A, Baier A, Peters MA, Dankbar B, Wille A, Drynda A, Mendoza H, Gay RE, Hay RT, Ink B, Gay S, Pap T
Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts.
Proceedings of the National Academy of Sciences of the United States of America 2007 Mar 20;104(12):5073-8
- Takahashi Y, Strunnikov A
In vivo modeling of polysumoylation uncovers targeting of Topoisomerase II to the nucleolus via optimal level of SUMO modification.
Chromosoma 2008 Apr;117(2):189-98