On the track of intramembrane clippers: the SPPL2a/b proteases caught in the act in animal models

• Published in: The FEBS journal 2023-05, Vol.290 (9), p.2306-2310
• Main Authors: Trávníčková, Květa, Stříšovský, Kvido
• Format: Article
• Language: English
• Subjects: Amyloid Precursor Protein Secretases - metabolism; Animal models; Animal tissues; Animals; Aspartic Acid Endopeptidases - metabolism; In vivo methods and tests; intramembrane protease; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Models, Animal; Protein turnover; Proteins; Proteolysis; signal peptide peptidase‐like; SNAP receptors; SNARE; Substrate specificity; Substrates; trafficking
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16663

In this issue, Ballin et al. report on their analysis of the substrate repertoire of SPPL2a and b intramembrane proteases. Based on the previous studies of their closest homologues, SPPL2c, SPPL3 and SPP, the authors hypothesized that SPPL2a/b proteases may cleave a subset of SNARE proteins. Indeed, four R‐SNARE proteins, VAMP1, 2, 3 and 4, were cleaved by SPPL2a/b, both in overexpression assays and at endogenous levels. These findings have been validated by analysis of SPPL2a/b double knock‐out mice tissues, which implicates these proteases in the regulation of SNARE protein turnover in vivo. The study of Ballin et al. also provides material for future studies of factors determining substrate specificity of SPPLs, as they cleave different subsets of the tail‐anchored SNARE proteins. Comment on: https://doi.org/10.1111/febs.16610 In this issue, Ballin et al. report the identification of new substrates of SPPL2a and b intramembrane proteases. A subset of R‐SNARE proteins, VAMP1, 2, 3 and 4, were found to be cleaved by SPPL2a/b in overexpression assays and at endogenous levels in mouse tissues. These findings implicate SPPL2a/b in the regulation of SNARE protein turnover and possibly trafficking, and provide material for future studies of substrate specificity of SPPLs. Comment on: https://doi.org/10.1111/febs.16610