Identification of Beta-TRCP1 Ubiquitin Ligase as a Novel Regulator of the SCAP-Mediated SREBP Pathway Activation

Dysregulation of lipid metabolism is associated with numerous metabolic disorders, including atherosclerosis, cardiovascular diseases, obesity, and diabetes. With the SREBP pathway being a central regulator of both lipid and cholesterol metabolism, advancement in understanding the pathway’s regulatory molecular mechanisms is imperative. Here, we have identified the E3 ubiquitin ligase β-TrCP1 as a competent regulator of the SREBP pathway. Through shRNA-mediated knockdown and CRISPR/Cas9-mediated gene editing, we identified phosphorylated SCAP, the SREBP cleavage activating protein, to be a new substrate of the SCF^β-TrCP1 complex. In this study, we have used different methods to examine the importance of β-TrCP1/SCAP interaction and the subsequent effect on the SREBP pathway regulation. These methods included in-vitro thermostability assay, in-vivo heat-shock, lipid, and cholesterol depletion/surplus, together with immunofluorescence microscopy. Unconventionally, this interaction appears to enhance the stability and functionality of the SCAP by promoting proper protein folding in the endoplasmic reticulum and preventing its aggregation. We further identified the role of β-TrCP1 in regulating the autophago-lysosomal degradation of misfolded SCAP, specifically under heat-shock and cellular stress.

In conclusion, the foundational discoveries presented in this study open a wide door for further exploration and necessary follow-up work. If this is confirmed, this research may very well point to a new paradigm in the SREBP regulatory dynamics – the β-TrCP1/SCAP axis regulation of the SREBP pathway. This underscores a potentially pivotal mechanistic interaction with profound implications for the regulation of lipid metabolism and future drug discovery.