MINIREVIEW
SREBPs: protein interaction and SREBPs
Ryuichiro Sato
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Japan
Introduction
The sterol regulatory element-binding protein
(SREBP) family members SREBP-1 and SREBP-2
are localized on the endoplasmic reticulum (ER) as
membrane proteins after being synthesized. Once the
intracellular cholesterol level is decreased, the
SREBPs subsequently move in vesicles to the Golgi
complex, where they are processed sequentially by
two proteases. These cleavage steps release the
mature forms of SREBPs, which enter the nucleus
and activate genes related to cholesterol and fatty
acid metabolism [1,2]. In both the cytoplasm and
nucleus, SREBPs associate with a variety of proteins.
This interaction determines their intracellular translo-
cation and stability, and also regulates their activities
as transcriptional factors.
Protein interaction on the ER and in the
cytosol
SREBPs are localized on the ER membrane, associat-
ing with another ER membrane protein, SREBP cleav-
age-activating protein (SCAP) (Fig. 1). SCAP has two
distinct domains. The N-terminal domain has eight
transmembrane helices, which include the so-called ste-
rol-sensing domain. This domain resembles sequences
in three other proteins that are postulated to interact
with sterols: HMG-CoA reductase, the Niemann–Pick
C1 protein, and Patched [3]. The C-terminal domain of

622 FEBS Journal 276 (2009) 622–627 ª 2008 The Author Journal compilation ª 2008 FEBS
become depleted in cholesterol, SCAP escorts SREBPs
from the ER to the Golgi apparatus, where two
proteases, designated site 1 protease (S1P) and site 2
protease (S2P), reside. In the Golgi apparatus, S1P, a
membrane-bound serine protease, cleaves SREBPs in
the luminal loop between their two membrane-span-
ning segments. The N-terminal domain is then released
from the membrane by S2P, a membrane-bound zinc
metalloproteinase. In the cytoplasm, the N-terminal
cleaved forms of SREBPs interact with importin-b,an
escort protein of nuclear proteins, and thereafter are
transported into the nucleus [5]. It is a quite character-
istic transport pathway, in that the nuclear import
occurs in the absence of importin-a. Furthermore, the
dimerization of SREBPs via the leucine zipper domain
is required for the interaction with importin-b [6]. In
the nucleus, SREBPs detach from importin-b, and
their transcription factor activities are regulated
through interaction with a variety of nuclear proteins.
Interaction with the ubiquitous
transcription factors Sp1 and NF-Y
in the nucleus
SREBPs were first discovered as transcription factors
that stimulate low-density lipoprotein (LDL) receptor
gene expression [7]. In the promoter of the LDL recep-
tor gene, a pair of essential elements exists to which a
ubiquitous transcription factor, Sp1, binds. An
SREBP-binding site, SRE, is closely located between
these two Sp1-binding sites, and all of these sites are

coactivator-1 (PGC-1) family of coactivators is of
particular importance in the control of liver metabo-
lism. PGC-1a stimulates mitochondrial biogenesis and
Fig. 1. SREBPs interact with SCAP or
importin-b in the cytoplasm. SREBPs local-
ized on the ER membrane associate with
another ER membrane protein, SCAP. This
complex is transported to the Golgi appara-
tus, where SREBPs are processed sequen-
tially by two proteases, S1P and S2P. The
cleaved forms of SREBPs, as homodimers,
interact with importin-b, which escorts them
to the nucleus.
R. Sato Protein interaction and SREBPs
FEBS Journal 276 (2009) 622–627 ª 2008 The Author Journal compilation ª 2008 FEBS 623
respiration, and modulates hepatic gluconeogenesis. In
contrast, PGC-1b, a transcriptional coactivator closely
related to PGC-1a, is highly induced in response to
short-term high-fat feeding in mice. PGC-1b interacts
with SREBPs, thereby inducing a broad program of
lipid metabolism, including de novo lipogenesis and
lipoprotein secretion [15]. This suggests, at least in
part, a mechanism through which dietary saturated
fats stimulate hyperlipidemia and atherogenesis.
SREBPs dock on PGC-1b at a domain that has no
counterpart in PGC-1a, and hence, PGC-1a does not
coactivate the SREBPs.
Protein modification of SREBPs
regulates their activities
In the nucleus, SREBPs are unstable and rapidly

the specific enzymes are distinct from those involved in
ubiquitination. Ubc9 is a SUMO-conjugating enzyme
(E2) that directly interacts with most sumoylated pro-
teins, including SREBPs [20]. In some cases, ubc9 itself
plays, to a certain extent, a SUMO E3-like role in the
absence of any E3 ligases. Unlike ubiquitination,
which requires phosphorylation near the ubiquitination
site, sumoylation competes with the phosphorylation
near the sumoylation site, which occurs in response to
growth factor stimuli [21]. This implies that growth
factor stimuli interfere with sumoylation, thereby
enhancing SREBP transcriptional activities, and lipid
synthesis required for cell growth. Sumoylated
SREBPs recruit a corepressor complex containing his-
tone deacetylase 3 to suppress their transcriptional
activities [21]. Histone deacetylase 3 is unable to
directly interact with SREBPs, but a certain subunit in
the corepressor complex, which is not yet identified, is
considered to be involved in the interaction.
SREBPs interact with activating
transcription factor-6 (ATF6) and
nuclear receptors to regulate their
transcriptional activities
ATF6 is an ER membrane-bound transcription factor
activated in response to ER stress. During the quies-
cent state, the C-terminus of ATF6 resides in the ER
lumen, with its N-terminus projecting into the cytosol.
Once unfolded or misfolded proteins accumulate in the
ER, ATF6 moves from the ER to the Golgi, where
both ATF6 and SREBPs are cleaved by S1P and S2P.

the HNF-4-binding site is responsible for the SREBP-1
inhibition. SREBPs and HNF-4 physically interact
through the N-terminal transactivation domain of
SREBP and the C-terminal ligand-binding domain of
HNF-4 [26]. HNF-4 recruits a coactivator, PGC-1a,
for its transcriptional activation. SREBPs interfere
with this recruitment of PGC-1a. Under fasting condi-
tions, HNF-4 and PGC-1a vigorously activate the
expression of gluconeogenic genes. In contrast, under
feeding conditions, SREBP-1c, the expression of which
is highly enhanced by insulin, might negatively regulate
HNF-4 transcriptional activity by competing with
PGC-1a, leading to a reduction of gluconeogenesis.
In contrast to the above findings, the transcriptional
activity of SREBPs is augmented by HNF-4 [27].
Overexpression of HNF-4 enhances the expression of
SREBP target genes in culture cells, but not through
the direct binding of HNF-4 to the promoters. HNF-4
interaction with SREBPs probably augments their
transcriptional activities due to HNF-4-mediated
recruitment of several coactivators, which are not
recruited by SREBPs alone, including PGC-1a. In the
liver and intestine, where lipid biosynthesis is quite
active and HNF-4 is exclusively expressed, the syner-
gistic activity of SREBPs and HNF-4 might cause
lipids to be distributed to other tissues that do not
have the capacity to biosynthesize sufficient lipids on
their own.
In a study aimed at identifing other nuclear receptor
family members affecting SREBP transcriptional activ-

response to a wide variety of physiological changes.
Conclusions
SREBPs are translocated from the ER to the Golgi
complex, where they are processed, and then trans-
ported into the nucleus. In this pathway, two interact-
Fig. 2. HNF-4 stimulates and LRH-1 suppresses the transcriptional activities of SREBP-1a and SREBP-2. HEK293 cells were transfected with
either 0.1 lg of pGAL4–SREBP1a (Gal4–DBD–SREBP1a) or pGAL4–SREBP2 (Gal4–DBD–SREBP2), 0.2 lg of pG5Luc containing five copies
of the Gal4-binding sites, and 10 ng of phRL-TK, together with increasing amounts of an expression vector for HNF-4a or LRH-1 (0.2 and
0.6 lg); they were then cultured in a medium containing 10% fetal bovine serum for 48 h. Luciferase assays were performed. The promoter
activities in the absence of pGAL4–SREBP1a or pGAL4–SREBP2 are represented as 1. All data are presented as means ± SD.
R. Sato Protein interaction and SREBPs
FEBS Journal 276 (2009) 622–627 ª 2008 The Author Journal compilation ª 2008 FEBS 625
ing proteins, SCAP and importin-b, play an important
role in determining the fate of SREBPs. In the nucleus,
multiple nuclear proteins form a complex with
SREBPs on their target gene promoters to regulate the
transcriptional activity. In addition, SREBPs interact
with ubiquitin- or SUMO-transfer enzymes, thereafter
being rapidly degraded or inactivated, respectively.
Some nuclear receptors and transcription factors also
associate with SREBPs in the nucleus. This association
exerts considerable physiological influence on the
expression of their target genes. Further studies will be
required to elucidate the more complex network
among the numerous transcription factors that regu-
late lipid and energy metabolism.
Acknowledgements
The author is grateful to K. Boru of Pacific Edit for
reviewing the manuscript.
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