SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond

Abstract

Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. SREBPs are controlled by multiple mechanisms at the level of mRNA synthesis, proteolytic activation, and transcriptional activity. In this review, we summarize the recent findings that contribute to the current understanding of the regulation of SREBPs and their physiologic roles in maintenance of lipid homeostasis, insulin signaling, innate immunity, and cancer development.

Figure 1. Proteolytic activation of SREBPs

Following synthesis on ER membranes, SREBP precursors bind to Scap through an interaction mediated by the C-terminal regulatory domain of the SREBP and the cytosolic C-terminal domain of Scap, which contains WD repeats. When cells are deprived of sterols, Scap escorts SREBPs from the ER to the Golgi by binding to the Sar1/Sec23/Sec24 complex of the COPII protein coat. In the Golgi, SREBP first encounters the Site-1 protease (S1P), which cleaves the SREBP in the lumenal loop, separating the protein into two membrane-bound halves. S1P-mediated cleavage renders the N-terminal half of SREBP a substrate for the Site-2 protease (S2P), which releases the bHLH-containing domain of SREBP by cleaving the intermediate near the cytosol-membrane boundary. Once released from membranes, transcriptionally active fragments of SREBPs migrate to the nucleus and bind to SREs in promotors of target genes to activate transcription.

Figure 2. Sterol-mediated regulation of ER-to-Golgi transport of Scap

In sterol-deprived cells, Loop 1 of Scap is bound to Loop 7 (A). This conformation allows Scap to bind to COPII, which triggers transport of Scap from ER to Golgi. When cholesterol accumulates in ER membranes, it binds to Loop 1 and induces a conformation change in the Scap SSD that increases its affinity for Insig (B). The binding of Insig triggers a second conformational change in the Scap SSD that leads to dissociation of Loop 1 and Loop 7. As a result, Scap no longer binds COPII and becomes trapped in ER membranes (C). 25-HC also promotes binding of Scap to Insigs, but through a distinct mechanism. 25-HC directly binds to Insig (D), increasing its affinity for the SSD of Scap. Binding to Insig induces a conformational change in Scap that prevents binding to COPII (E).

Figure 3. UFA-mediated inhibition of ER-to-Golgi transport of Scap/SREBP

In cells deprived of UFAs, Insig-1 is poly-ubiquitinated by gp78 and bound by the p97 adapter Ubxd8. Ubiquitinated Insig-1 is extracted from ER membranes through p97 and delivered to proteasomes for degradation. In the absence of Insig-1, the Scap escorts SREBP from the ER to the Golgi for proteolytic activation. Ubxd8 polymerizes upon binding to UFAs, resulting in its dissociation from Insig-1. As a result, Insig-1 becomes stabilized and blocks proteolytic activation of SREBPs by binding to Scap.

Figure 4. Insulin-mediated regulation of the SREBP pathway

Insulin modulates the SREBP pathway through transcriptional and post-transcriptional mechanisms that require the action of mTOR. Insulin-mediate activation of mTOR leads to phosphorylation of S6K1, which enhances cleavage of SREBP-1c by activating an unknown target. At the same time, mTOR activates an unknown factor that in turn modulates the LXR/C-EBPβ complex to enhance transcription of the SREBP-1c gene. Finally, mTOR phosphorylates Lipin-1, relieving its inhibition of SREBP transcriptional activity.