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

• An Escherichia coli open reading frame, yaeL, encodes a predicted homolog of human site-2 protease (S2P), a putative membrane-bound zinc metalloproteinase involved in the proteolytic activation of regulatory factors for sterol biosynthesis and for stress responses [8].

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

• Both the NH(2) and COOH termini of S2P face the cytosol [9].
• Here, we use protease protection and glycosylation site mapping to define the topology of S2P in ER membranes [9].
• The parental hamster cell line (M19 cells) lacks its own nSREBPs, owing to a deletion in the gene encoding the Site-2 protease, which releases nSREBPs from cell membranes [13].

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

• Amyloid precursor protein processing in sterol regulatory element-binding protein site 2 protease-deficient Chinese hamster ovary cells [16].

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].

References