The endoplasmic reticulum (ER)-resident intramembrane rhomboid protease RHBDL4 generates metastable protein fragments and together with the ER-associated degradation (ERAD) machinery provides a clearance mechanism for aberrant and surplus proteins. However, the endogenous substrate spectrum and with that the role of RHBDL4 in physiological ERAD is mainly unknown. Here, we use a substrate trapping approach in combination with quantitative proteomics to identify physiological RHBDL4 substrates. This revealed oligosaccharyltransferase (OST) complex subunits such as the catalytic active subunit STT3A as substrates for the RHBDL4-dependent ERAD pathway. RHBDL4-catalysed cleavage inactivates OST subunits by triggering dislocation into the cytoplasm and subsequent proteasomal degradation. RHBDL4 thereby controls the abundance and activity of OST, suggesting a novel link between the ERAD machinery and glycosylation tuning.
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Rhomboid proteases are ubiquitous intramembrane serine proteases that can cleave transmembrane substrates within lipid bilayers. They exhibit many and diverse functions, such as but not limited to, growth factor signaling, immune and inflammatory response, protein quality control, and parasitic invasion. Human rhomboid protease RHBDL4 has been demonstrated to play a critical role in removing misfolded proteins from the Endoplasmic Reticulum and is implicated in severe diseases such as various cancers and Alzheimer's disease.
View Article and Find Full Text PDFActivity-Based Protein Profiling of RHBDL4 Reveals Proteolysis of the Enzyme and a Distinct Inhibitor Profile.
ACS Chem Biol
August 2024
Department of Chemistry and Biochemistry, Oberlin College, Oberlin, Ohio 44074, United States.
Article Synopsis
- Rhomboid proteases, including human RHBDL4, are important due to their roles in protein degradation and disease, particularly cancer, but effective chemical tools to study them have been lacking.
- An activity-based protein profiling (ABPP) assay was developed specifically for RHBDL4, revealing that it undergoes processing to form active proteoforms with shorter C-termini in cells.
- The study also identified specific chemical compounds that can inhibit RHBDL4 and showed that there are differences in inhibitor preferences between RHBDL4 and another rhomboid protease called PARL, highlighting the utility of ABPP for enzyme characterization and selective targeting.
Eta-secretase-like processing of the amyloid precursor protein (APP) by the rhomboid protease RHBDL4.
J Biol Chem
August 2024
Department of Pharmacology and Therapeutics, McGill University, Bellini Life Sciences, Complex, Montreal, Quebec, Canada; School of Biomedical Sciences (SBMS), McGill University, Bellini Life Sciences Complex, Montreal, Quebec, Canada; Centre de Recherche en Biologie Structurale (CRBS), McGill University, Montréal, Québec, Canada. Electronic address:
The amyloid precursor protein (APP) is a key protein in Alzheimer's disease synthesized in the endoplasmic reticulum (ER) and translocated to the plasma membrane where it undergoes proteolytic cleavages by several proteases. Conversely, to other known proteases, we previously elucidated rhomboid protease RHBDL4 as a novel APP processing enzyme where several cleavages likely occur already in the ER. Interestingly, the pattern of RHBDL4-derived large APP C-terminal fragments resembles those generated by the η-secretase or MT5-MMP, which was described to generate so-called Aη fragments.
View Article and Find Full Text PDFLoss of the APP regulator RHBDL4 preserves memory in an Alzheimer's disease mouse model.
bioRxiv
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Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada H3G 0B1.
Characteristic cerebral pathological changes of Alzheimer's disease (AD) such as glucose hypometabolism or the accumulation of cleavage products of the amyloid precursor protein (APP), known as Aβ peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded protein response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in the UPR by targeting proteins for proteasomal degradation.
View Article and Find Full Text PDFThe toll-like receptor 4 (TLR4) is a central regulator of innate immunity that primarily recognizes bacterial lipopolysaccharide cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4 triggers degradation of TLR4's trafficking factor TMED7.
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