Proteolytic Control of Lipid Metabolism

Abstract

Synthesis and regulation of lipid levels and identities is critical for a wide variety of cellular functions, including structural and morphological properties of organelles, energy storage, signaling, and stability and function of membrane proteins. Proteolytic cleavage events regulate and/or influence some of these lipid metabolic processes and as a result help modulate their pleiotropic cellular functions. Proteins involved in lipid regulation are proteolytically cleaved for the purpose of their relocalization, processing, turnover, and quality control, among others. The scope of this review includes proteolytic events governing cellular lipid dynamics. After an initial discussion of the classic example of sterol regulatory element-binding proteins, our focus will shift to the mitochondrion, where a range of proteolytic events are critical for normal mitochondrial phospholipid metabolism and enforcing quality control therein. Recently, mitochondrial phospholipid metabolic pathways have been implicated as important for the proliferative capacity of cancers. Thus, the assorted proteases that regulate, monitor, or influence the activity of proteins that are important for phospholipid metabolism represent attractive targets to be manipulated for research purposes and clinical applications.

Figure 1.

Regulated proteolytic activation of SREBPs. (A) Sterol regulatory element binding proteins (SREBPs) are synthesized as inactive precursors and retained in the ER. In mammals, SCAP responds to low cholesterol levels by releasing INSIGs and escorts SREBP to the Golgi. Flies, which lack INSIG orthologues, allow fly SREBP to move to the Golgi in response to low levels of PE. Once in the Golgi, SREBP is sequentially cleaved by S1P and S2P to release nuclear SREBP (nSREBP). nSREBP moves to the nucleus, where it activates the transcription of SRE-containing genes. (B) In fission yeast, hypoxia triggers proteolytic activation of Sre1. When oxygen levels are low, Scp1 escorts Sre1 to the Golgi, where it is then cleaved by Rbd2 in a process that is facilitated by Cdc48. Following its cleavage by an unidentified second protease, Sre1N is released to the nucleus to activate transcription of hypoxic response genes.

Figure 2.

Localization of mitochondrial proteases. Yeast proteins have only the first letter capitalized, and mammalian proteins are all capitalized. Examples of notable substrates for each protease are listed in the gray box associated with each protease.

Figure 3.

Proteolytic regulation of lipid transfer proteins in yeast. When CL levels are low, Ups1/Mdm35 transfers PA across the IMS to be converted to CL by a multistep biosynthetic pathway. When CL levels are high, Ups1/Mdm35 is sequestered at the IM by CL and Ups1 is degraded by Yme1 and Atp23. These proteases also degrade uncomplexed Ups1. The dynamic association of Ups1/Mdm35 is important for PA transport, and it is unclear after how many rounds of lipid transfer Ups1 dissociates from Mdm35 and is degraded. Similarly, Ups2/Mdm35 transfers PS across the IMS to be converted to PE by Psd1. Uncomplexed Ups2 is also degraded by Yme1, and the number of lipid transfer events of which the complex is capable has also yet to be determined. CL sequestration of Ups1/Mdm35 at the IM has yet to be formally tested in vivo.

Figure 4.

Dual targeting of the mammalian lipid-transfer protein STARD7 to the cytosol and mitochondrial IMS. STARD7 precursors are translated in the cytosol and threaded through the translocon of the OM (TOM), the common entry gate into mitochondria. If the precursor engages TIM23 in the IM, it is laterally sorted into this lipid bilayer prior to being cleaved by PARL. The released mature STARD7 is retained in the IMS, where it mediates the transport of PC across the IMS. If the STARD7 precursor is cleaved by PARL independent of TIM23, then it is released to the cytosol, where it facilitates the uptake of PC to the OM.