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Gene Review

MBTPS2  -  membrane-bound transcription factor...

Homo sapiens

Synonyms: BRESEK, Endopeptidase S2P, IFAP, KFSD, KFSDX, ...
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Disease relevance of MBTPS2

  • Escherichia coli YaeL (EcfE) is a homolog of human site-2 protease (S2P), a membrane-bound zinc metalloprotease involved in regulated intramembrane proteolysis [1].
  • mbtps2 is the causal gene of the ichthyosis follicularis with atrichia and photophobia syndrome (IFAP), with associated mutations: p.M87I, p.W226L, p.H227L, p.R429H, p.F475S [2]
  • mbtps2 is the causal gene of Keratosis Follicularis Spinulosa Decalvans (KFSD), with associated mutations: p.N508S [3]
  • mbtps2 is the causal gene of the BRESEK/BRESHECK syndrome, with associated mutations: p.R429H [4]

High impact information on MBTPS2

  • To elucidate the requirements for IRE1alpha and ATF6 for signaling the mammalian UPR, we identified a UPR reporter gene that was defective for induction in IRE1alpha-null mouse embryonic fibroblasts and S2P-deficient Chinese hamster ovary (CHO) cells [5].
  • In higher eukaryotic cells, the UPR also induces site-2 protease (S2P)-mediated cleavage of ER-localized ATF6 to generate an N-terminal fragment that activates transcription of UPR genes [5].
  • We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis [6].
  • ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P [6].
  • Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease [7].

Chemical compound and disease context of MBTPS2


Biological context of MBTPS2

  • The hydrophobicity of these sequences suggests that the active site of S2P is located within the membrane in an ideal position to cleave its target, a Leu-Cys bond in the first transmembrane helix of SREBPs [9].
  • Although it is well established that p90ATF6 activation requires transit from the ER to the Golgi, where it is cleaved by the S1P/S2P protease system to generate a nuclear form p60ATF6 that acts as a transcriptional activator, the functional significance of p90ATF6 N-linked glycosylation is unknown [10].
  • Argentina B. bovis strains R1A and S2P have msa-1 genes with amino acid sequences that are 98.8% identical to each other, and antibodies against S2P MSA-1 cross-react with native R1A MSA-1 [11].
  • Site-2 protease regulated intramembrane proteolysis: sequence homologs suggest an ancient signaling cascade [12].
  • S2P relatives were identified in genomes from Bacteria, Archaea, and Eukaryota including protists, plants, fungi, and animals [12].

Anatomical context of MBTPS2


Associations of MBTPS2 with chemical compounds

  • ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively [6].
  • The human S2P gene was cloned by complementation of mutant CHO cells that cannot cleave SREBPs at Site-2 and are cholesterol auxotrophs [14].
  • Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins [9].
  • Multivariate analysis identified continuous SvO2 monitoring as a factor favoring S1P survival (P=0.02) and use of POB as a factor favoring survival to S2P (P=0.003) [15].

Physical interactions of MBTPS2


Other interactions of MBTPS2

  • We propose a model in which the asparagine-proline sequence serves as an NH(2)-terminal cap for a portion of the transmembrane alpha-helix of SREBP, allowing the remainder of the alpha-helix to unwind partially to expose the peptide bond for cleavage by S2P [7].
  • In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P [7].
  • Our results indicate that YY2 is a retroposed copy of YY1 that has been inserted into another gene locus named Mbtps2 (membrane-bound transcription factor protease site 2) [17].



  1. YaeL (EcfE) activates the sigma(E) pathway of stress response through a site-2 cleavage of anti-sigma(E), RseA. Kanehara, K., Ito, K., Akiyama, Y. Genes Dev. (2002) [Pubmed]
  2. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Oeffner, F., Fischer, G., Happle, R., König, A., Betz, R.C., Bornholdt, D., Neidel, U., Boente Mdel, C., Redler, S., Romero-Gomez, J., Salhi, A., Vera-Casaño, A., Weirich, C., Grzeschik, K.H. Am. J. Hum. Genet. (2009) [Pubmed]
  3. Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2. Aten, E., Brasz, L.C., Bornholdt, D., Hooijkaas, I.B., Porteous, M.E., Sybert, V.P., Vermeer, M.H., Vossen, R.H., van der Wielen, M.J., Bakker, E., Breuning, M.H., Grzeschik, K.H., Oosterwijk, J.C., den Dunnen, J.T. Hum. Mutat. (2010) [Pubmed]
  4. MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Naiki, M., Mizuno, S., Yamada, K., Yamada, Y., Kimura, R., Oshiro, M., Okamoto, N., Makita, Y., Seishima, M., Wakamatsu, N. Am. J. Med. Genet. A. (2011) [Pubmed]
  5. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Lee, K., Tirasophon, W., Shen, X., Michalak, M., Prywes, R., Okada, T., Yoshida, H., Mori, K., Kaufman, R.J. Genes Dev. (2002) [Pubmed]
  6. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Ye, J., Rawson, R.B., Komuro, R., Chen, X., Davé, U.P., Prywes, R., Brown, M.S., Goldstein, J.L. Mol. Cell (2000) [Pubmed]
  7. Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease. Ye, J., Davé, U.P., Grishin, N.V., Goldstein, J.L., Brown, M.S. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  8. Characterization of the yaeL gene product and its S2P-protease motifs in Escherichia coli. Kanehara, K., Akiyama, Y., Ito, K. Gene (2001) [Pubmed]
  9. Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins. Zelenski, N.G., Rawson, R.B., Brown, M.S., Goldstein, J.L. J. Biol. Chem. (1999) [Pubmed]
  10. Underglycosylation of ATF6 as a novel sensing mechanism for activation of the unfolded protein response. Hong, M., Luo, S., Baumeister, P., Huang, J.M., Gogia, R.K., Li, M., Lee, A.S. J. Biol. Chem. (2004) [Pubmed]
  11. Characterization of allelic variation in the Babesia bovis merozoite surface antigen 1 (MSA-1) locus and identification of a cross-reactive inhibition-sensitive MSA-1 epitope. Suarez, C.E., Florin-Christensen, M., Hines, S.A., Palmer, G.H., Brown, W.C., McElwain, T.F. Infect. Immun. (2000) [Pubmed]
  12. Site-2 protease regulated intramembrane proteolysis: sequence homologs suggest an ancient signaling cascade. Kinch, L.N., Ginalski, K., Grishin, N.V. Protein Sci. (2006) [Pubmed]
  13. Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins. Pai, J.T., Guryev, O., Brown, M.S., Goldstein, J.L. J. Biol. Chem. (1998) [Pubmed]
  14. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Rawson, R.B., Zelenski, N.G., Nijhawan, D., Ye, J., Sakai, J., Hasan, M.T., Chang, T.Y., Brown, M.S., Goldstein, J.L. Mol. Cell (1997) [Pubmed]
  15. Improved survival of patients undergoing palliation of hypoplastic left heart syndrome: lessons learned from 115 consecutive patients. Tweddell, J.S., Hoffman, G.M., Mussatto, K.A., Fedderly, R.T., Berger, S., Jaquiss, R.D., Ghanayem, N.S., Frisbee, S.J., Litwin, S.B. Circulation (2002) [Pubmed]
  16. Amyloid precursor protein processing in sterol regulatory element-binding protein site 2 protease-deficient Chinese hamster ovary cells. Ross, S.L., Martin, F., Simonet, L., Jacobsen, F., Deshpande, R., Vassar, R., Bennett, B., Luo, Y., Wooden, S., Hu, S., Citron, M., Burgess, T.L. J. Biol. Chem. (1998) [Pubmed]
  17. Rapid evolution of a recently retroposed transcription factor YY2 in mammalian genomes. Luo, C., Lu, X., Stubbs, L., Kim, J. Genomics (2006) [Pubmed]
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