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 [1], [2].
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) [1], [3], [4], [5], [6]. Cleavage of the
SUMO-1 from the target protein is mediated by
SENP1 peptidase (isopeptidase cleavage) [1].
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 [7]. 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 [8].
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 [4], [9].
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 [4], [6].
RanBP2 promotes sumoylation of Ran GTPase activating
protein 1 (RanGAP1), stimulates
RanGAP1 functions and increases the accumulation of properly
folded RanGAP1 protein [10], [11], [12].
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 [13].
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 [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30].
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