{"gene":"HM13","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2004,"finding":"C. elegans imp-2 (ortholog of human HM13/SPP) is functionally distinct from presenilins: knockdown causes embryonic death and molting defects but does NOT promote Notch (lin-12, glp-1) proteolysis or signaling, placing IMP/SPP outside the presenilin-Notch pathway.","method":"C. elegans RNAi knockdown with phenotypic readout (embryonic lethality, molting defect); genetic epistasis with lin-12/glp-1 Notch pathway","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined phenotype plus epistasis analysis, single lab but two orthogonal approaches (phenotype + pathway placement)","pmids":["15469912"],"is_preprint":false},{"year":2004,"finding":"The imp-2/HM13 developmental function in C. elegans is linked to a lipid/lipoprotein receptor-mediated pathway: the molting defect caused by Ce-imp-2 depletion was mimicked by cholesterol depletion or disruption of Ce-lrp-1 (megalin/LRP ortholog) and partially suppressed by a Ce-lrp-1 derivative, placing IMP/SPP upstream of or parallel to the LRP cholesterol/lipoprotein endocytosis pathway.","method":"Genetic epistasis in C. elegans: RNAi of Ce-imp-2 combined with cholesterol depletion and Ce-lrp-1 manipulation; partial rescue by Ce-lrp-1 derivative expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with rescue experiment, single lab, multiple genetic conditions tested","pmids":["15469912"],"is_preprint":false},{"year":2004,"finding":"Human HM13/IMP1 (SPP) possesses endoproteolytic activity and cleaves the presenilin-1 holoprotein within its transmembrane domain in cultured cells; mutation of evolutionarily invariant residues (putative catalytic aspartates) in hIMP1 abolishes this cleavage, and specific gamma-secretase inhibitors also block the activity, demonstrating that HM13/SPP is a bi-aspartic intramembrane protease capable of cleaving multipass transmembrane substrates.","method":"Co-expression in cultured cells; active-site mutagenesis of invariant aspartate residues; pharmacological inhibition with gamma-secretase inhibitors; endoproteolysis assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in-cell enzymatic activity assay combined with active-site mutagenesis and pharmacological inhibition, single lab but multiple orthogonal methods","pmids":["14741365"],"is_preprint":false},{"year":2017,"finding":"HM13/SPP promotes secretion of cytokines from EGFRvIII-expressing glioblastoma cells: SPP knockdown significantly reduced cytokine levels in EGFRvIII conditioned media and attenuated intracellular maturation of TGF-β1, indicating SPP acts in the endoplasmic reticulum to facilitate processing and secretion of cytokines, thereby promoting tumor progression in vivo.","method":"siRNA knockdown of HM13/SPP in glioblastoma cells; human cytokine antibody array; intracellular maturation tracking of TGF-β1; mouse xenograft tumor model","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular readout (cytokine secretion profiling) plus in vivo validation, single lab","pmids":["28198167"],"is_preprint":false},{"year":2022,"finding":"HM13 knockdown in breast cancer cells activates autophagy by inducing endoplasmic reticulum (ER) stress and inhibits the PI3K-AKT-mTOR signaling pathway, placing HM13 as a suppressor of autophagy acting through the PI3K-AKT-mTOR axis in the ER context.","method":"siRNA knockdown of HM13 in breast cancer cells; autophagy assays; ER stress markers; PI3K-AKT-mTOR pathway activity assays; xenograft tumor model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple pathway readouts and in vivo confirmation, single lab","pmids":["36153332"],"is_preprint":false}],"current_model":"HM13 (SPP/IMP1) is a bi-aspartic intramembrane protease resident in the endoplasmic reticulum that cleaves type-I and multipass transmembrane substrates (including presenilin-1 holoprotein) via catalytic aspartate residues; it is functionally distinct from presenilins in that it does not promote Notch signaling, instead acting in a pathway linked to lipid/lipoprotein receptor-mediated endocytosis during development, and in cancer contexts it facilitates cytokine secretion and suppresses autophagy by modulating ER stress and the PI3K-AKT-mTOR pathway."},"narrative":{"mechanistic_narrative":"HM13 (SPP/IMP1) is a bi-aspartic intramembrane protease of the endoplasmic reticulum that cleaves transmembrane substrates through invariant catalytic aspartate residues, demonstrated by its endoproteolysis of the presenilin-1 holoprotein within its transmembrane domain and the loss of this activity upon active-site mutagenesis or gamma-secretase inhibitor treatment [PMID:14741365]. Despite the shared catalytic chemistry, HM13 is functionally distinct from presenilins: its ortholog does not promote Notch proteolysis or signaling but is instead required for development, where loss causes embryonic lethality and molting defects linked to a lipid/lipoprotein receptor (LRP/megalin) endocytosis pathway [PMID:15469912]. In cancer contexts HM13 operates in the ER to facilitate intracellular maturation and secretion of cytokines including TGF-β1, promoting tumor progression [PMID:28198167], and to suppress autophagy by restraining ER stress and sustaining PI3K-AKT-mTOR signaling [PMID:36153332]. The full catalog of physiological transmembrane substrates beyond presenilin-1 has not been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Established that the IMP/SPP family is mechanistically separable from presenilins, answering whether this protease functions within the canonical presenilin-Notch pathway.","evidence":"C. elegans imp-2 RNAi knockdown with phenotypic readout and genetic epistasis against lin-12/glp-1 Notch signaling","pmids":["15469912"],"confidence":"Medium","gaps":["Did not identify the protease substrate responsible for the developmental phenotype","Notch independence shown genetically but not biochemically in human cells"]},{"year":2004,"claim":"Placed HM13's developmental role within a lipid/lipoprotein receptor endocytosis pathway, providing the first physiological context for its in vivo function.","evidence":"C. elegans epistasis combining imp-2 RNAi with cholesterol depletion and Ce-lrp-1 manipulation, with partial rescue by an Ce-lrp-1 derivative","pmids":["15469912"],"confidence":"Medium","gaps":["Whether HM13 acts directly on LRP/megalin or upstream is unresolved","No molecular substrate linking the protease activity to cholesterol/lipoprotein endocytosis identified"]},{"year":2004,"claim":"Defined HM13 as a bi-aspartic intramembrane protease, answering the core question of its catalytic mechanism and substrate range.","evidence":"Co-expression endoproteolysis assay of presenilin-1 holoprotein in cultured cells with active-site aspartate mutagenesis and gamma-secretase inhibitor blockade","pmids":["14741365"],"confidence":"High","gaps":["Physiological substrate repertoire beyond presenilin-1 not defined","No structural model of the catalytic mechanism"]},{"year":2017,"claim":"Connected HM13's ER protease activity to a secretory function, showing it facilitates cytokine processing and release to drive tumor progression.","evidence":"siRNA knockdown in EGFRvIII glioblastoma cells with cytokine antibody array, TGF-β1 maturation tracking, and mouse xenograft","pmids":["28198167"],"confidence":"Medium","gaps":["Whether cytokine maturation requires HM13 proteolytic activity or a non-catalytic role is unclear","Direct substrate cleaved by HM13 in the secretory pathway not identified"]},{"year":2022,"claim":"Identified HM13 as a suppressor of autophagy, linking its ER function to the PI3K-AKT-mTOR axis and ER stress control.","evidence":"siRNA knockdown in breast cancer cells with autophagy and ER stress markers, PI3K-AKT-mTOR activity assays, and xenograft model","pmids":["36153332"],"confidence":"Medium","gaps":["Mechanism connecting HM13 protease activity to ER stress and mTOR signaling not defined","Direct molecular intermediate between HM13 and the PI3K-AKT-mTOR pathway unknown"]},{"year":null,"claim":"The physiological transmembrane substrates of HM13 and the mechanism linking its intramembrane proteolysis to cytokine secretion, autophagy, and lipoprotein endocytosis remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No endogenous substrate beyond presenilin-1 characterized","Catalytic requirement for the cancer-associated phenotypes not established","No structural basis for substrate selection"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]}],"complexes":[],"partners":["PSEN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TCT9","full_name":"Signal peptide peptidase","aliases":["Intramembrane protease 1","IMP-1","IMPAS-1","hIMP1","Minor histocompatibility antigen H13","Presenilin-like protein 3","Signal peptide peptidase-like 1"],"length_aa":377,"mass_kda":41.5,"function":"Catalyzes intramembrane proteolysis of signal peptides that have been removed from precursors of secretory and membrane proteins, resulting in the release of the fragment from the ER membrane into the cytoplasm (PubMed:12077416). Required to generate lymphocyte cell surface (HLA-E) epitopes derived from MHC class I signal peptides (PubMed:11714810). May be necessary for the removal of the signal peptide that remains attached to the hepatitis C virus core protein after the initial proteolytic processing of the polyprotein (PubMed:12145199). Involved in the intramembrane cleavage of the integral membrane protein PSEN1 (PubMed:11714810, PubMed:12077416, PubMed:14741365). Cleaves the integral membrane protein XBP1 isoform 1 in a DERL1/RNF139-dependent manner (PubMed:25239945). May play a role in graft rejection (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TCT9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HM13","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/HM13","total_profiled":1310},"omim":[{"mim_id":"607106","title":"MINOR HISTOCOMPATIBILITY 13; HM13","url":"https://www.omim.org/entry/607106"},{"mim_id":"603046","title":"RING FINGER PROTEIN 139; RNF139","url":"https://www.omim.org/entry/603046"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HM13"},"hgnc":{"alias_symbol":["H13","dJ324O17.1","SPP","PSL3","IMP1","IMPAS","PSENL3","SPPL1"],"prev_symbol":["HM13-IT1"]},"alphafold":{"accession":"Q8TCT9","domains":[{"cath_id":"-","chopping":"28-106_202-348","consensus_level":"high","plddt":90.907,"start":28,"end":348}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCT9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCT9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCT9-F1-predicted_aligned_error_v6.png","plddt_mean":82.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HM13","jax_strain_url":"https://www.jax.org/strain/search?query=HM13"},"sequence":{"accession":"Q8TCT9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TCT9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TCT9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCT9"}},"corpus_meta":[{"pmid":"12692099","id":"PMC_12692099","title":"Acanthamoeba spp. as agents of disease in humans.","date":"2003","source":"Clinical microbiology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12692099","citation_count":983,"is_preprint":false},{"pmid":"9343343","id":"PMC_9343343","title":"Xenorhabdus and Photorhabdus spp.: bugs that kill bugs.","date":"1997","source":"Annual review of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9343343","citation_count":376,"is_preprint":false},{"pmid":"21976604","id":"PMC_21976604","title":"Current knowledge of Trichosporon spp. and Trichosporonosis.","date":"2011","source":"Clinical microbiology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/21976604","citation_count":376,"is_preprint":false},{"pmid":"1779932","id":"PMC_1779932","title":"The biology of Giardia spp.","date":"1991","source":"Microbiological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/1779932","citation_count":355,"is_preprint":false},{"pmid":"12174081","id":"PMC_12174081","title":"Adhesion in Candida spp.","date":"2002","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12174081","citation_count":258,"is_preprint":false},{"pmid":"14711629","id":"PMC_14711629","title":"Campylobacter spp., Giardia spp., Cryptosporidium spp., noroviruses, and indicator organisms in surface water in southwestern Finland, 2000-2001.","date":"2004","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/14711629","citation_count":176,"is_preprint":false},{"pmid":"30003864","id":"PMC_30003864","title":"Antimicrobial Resistance in Mycoplasma spp.","date":"2018","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/30003864","citation_count":161,"is_preprint":false},{"pmid":"19216105","id":"PMC_19216105","title":"Quantification of Bifidobacterium spp. and Lactobacillus spp. in rat fecal samples by real-time PCR.","date":"2008","source":"Microbiological research","url":"https://pubmed.ncbi.nlm.nih.gov/19216105","citation_count":148,"is_preprint":false},{"pmid":"16040999","id":"PMC_16040999","title":"Surfaceome of Leptospira spp.","date":"2005","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/16040999","citation_count":132,"is_preprint":false},{"pmid":"30687275","id":"PMC_30687275","title":"Sulfur Oxidation in the Acidophilic Autotrophic Acidithiobacillus spp.","date":"2019","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30687275","citation_count":126,"is_preprint":false},{"pmid":"30101740","id":"PMC_30101740","title":"Antimicrobial Resistance in Acinetobacter spp. and Pseudomonas spp.","date":"2018","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/30101740","citation_count":124,"is_preprint":false},{"pmid":"12437090","id":"PMC_12437090","title":"Extracellular proteases of Staphylococcus spp.","date":"2002","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12437090","citation_count":116,"is_preprint":false},{"pmid":"21762494","id":"PMC_21762494","title":"Occurrence of Babesia spp., Rickettsia spp. and Bartonella spp. in Ixodes ricinus in Bavarian public parks, Germany.","date":"2011","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/21762494","citation_count":101,"is_preprint":false},{"pmid":"6090419","id":"PMC_6090419","title":"Aerobactin genes in Shigella spp.","date":"1984","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/6090419","citation_count":95,"is_preprint":false},{"pmid":"20202410","id":"PMC_20202410","title":"Bartonella spp. transmission by ticks not established.","date":"2010","source":"Emerging infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20202410","citation_count":93,"is_preprint":false},{"pmid":"18987885","id":"PMC_18987885","title":"Functional genes and proteins of Trichinella spp.","date":"2008","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/18987885","citation_count":86,"is_preprint":false},{"pmid":"21122216","id":"PMC_21122216","title":"Bartonella spp. in bats, Kenya.","date":"2010","source":"Emerging infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21122216","citation_count":86,"is_preprint":false},{"pmid":"29623873","id":"PMC_29623873","title":"Antimicrobial Resistance in Campylobacter spp.","date":"2018","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/29623873","citation_count":85,"is_preprint":false},{"pmid":"8821589","id":"PMC_8821589","title":"Quinolone resistance and Campylobacter spp.","date":"1995","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/8821589","citation_count":78,"is_preprint":false},{"pmid":"1475519","id":"PMC_1475519","title":"Antigenic variation and strain heterogeneity in Borrelia spp.","date":"1992","source":"Research in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1475519","citation_count":75,"is_preprint":false},{"pmid":"32555720","id":"PMC_32555720","title":"Genomic diversity of bacteriophages infecting Microbacterium spp.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32555720","citation_count":67,"is_preprint":false},{"pmid":"20697287","id":"PMC_20697287","title":"Bacteroides spp. and diarrhea.","date":"2010","source":"Current opinion in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20697287","citation_count":65,"is_preprint":false},{"pmid":"3450286","id":"PMC_3450286","title":"Reiterated DNA sequences in Rhizobium and Agrobacterium spp.","date":"1987","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/3450286","citation_count":65,"is_preprint":false},{"pmid":"30802650","id":"PMC_30802650","title":"Prevalence of antimicrobial resistance genes in Bacteroides spp. and Prevotella spp. Dutch clinical isolates.","date":"2019","source":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30802650","citation_count":63,"is_preprint":false},{"pmid":"8767704","id":"PMC_8767704","title":"Interactions between professional phagocytes and Brucella spp.","date":"1996","source":"Microbiologia (Madrid, Spain)","url":"https://pubmed.ncbi.nlm.nih.gov/8767704","citation_count":62,"is_preprint":false},{"pmid":"17641648","id":"PMC_17641648","title":"Single protein production (SPP) system in Escherichia coli.","date":"2007","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/17641648","citation_count":55,"is_preprint":false},{"pmid":"28655571","id":"PMC_28655571","title":"Zoonotic potential of Helicobacter spp.","date":"2017","source":"Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/28655571","citation_count":54,"is_preprint":false},{"pmid":"16007464","id":"PMC_16007464","title":"Simultaneous differentiation between Theileria spp. and Babesia spp. on stained blood smear using PCR.","date":"2005","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/16007464","citation_count":54,"is_preprint":false},{"pmid":"29932497","id":"PMC_29932497","title":"Detection of Babesia spp., Theileria spp. and Anaplasma ovis in Border Regions, northwestern China.","date":"2018","source":"Transboundary and emerging diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29932497","citation_count":52,"is_preprint":false},{"pmid":"24831516","id":"PMC_24831516","title":"Hemoglobin uptake by Paracoccidioides spp. is receptor-mediated.","date":"2014","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24831516","citation_count":52,"is_preprint":false},{"pmid":"25062275","id":"PMC_25062275","title":"Leptospira spp. in rodents and shrews in Germany.","date":"2014","source":"International journal of environmental research and public health","url":"https://pubmed.ncbi.nlm.nih.gov/25062275","citation_count":51,"is_preprint":false},{"pmid":"11376052","id":"PMC_11376052","title":"Coinfection of enteric Helicobacter spp. and Campylobacter spp. in cats.","date":"2001","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11376052","citation_count":51,"is_preprint":false},{"pmid":"15469912","id":"PMC_15469912","title":"The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15469912","citation_count":50,"is_preprint":false},{"pmid":"10759417","id":"PMC_10759417","title":"Molecular and genetic analyses of Actinomyces spp.","date":"1999","source":"Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists","url":"https://pubmed.ncbi.nlm.nih.gov/10759417","citation_count":50,"is_preprint":false},{"pmid":"1791425","id":"PMC_1791425","title":"Transformation and allelic replacement in Francisella spp.","date":"1991","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1791425","citation_count":50,"is_preprint":false},{"pmid":"33142619","id":"PMC_33142619","title":"Pullulan biosynthesis and its regulation in Aureobasidium spp.","date":"2020","source":"Carbohydrate polymers","url":"https://pubmed.ncbi.nlm.nih.gov/33142619","citation_count":49,"is_preprint":false},{"pmid":"32365968","id":"PMC_32365968","title":"Chemistry and Reactivity of Tannins in Vitis spp.: A Review.","date":"2020","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32365968","citation_count":47,"is_preprint":false},{"pmid":"26985924","id":"PMC_26985924","title":"Salt stress alters DNA methylation levels in alfalfa (Medicago spp).","date":"2016","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26985924","citation_count":46,"is_preprint":false},{"pmid":"14740910","id":"PMC_14740910","title":"Molecular phylogeny and surface morphology of marine aseptate gregarines (Apicomplexa): Selenidium spp. and Lecudina spp.","date":"2003","source":"The Journal of parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/14740910","citation_count":44,"is_preprint":false},{"pmid":"30419024","id":"PMC_30419024","title":"Human-pathogenic Anaplasma spp., and Rickettsia spp. in animals in Xi'an, China.","date":"2018","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30419024","citation_count":42,"is_preprint":false},{"pmid":"32722172","id":"PMC_32722172","title":"The Medical Relevance of Fusarium spp.","date":"2020","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32722172","citation_count":39,"is_preprint":false},{"pmid":"24619360","id":"PMC_24619360","title":"Stachybotrys spp. and the guttation phenomenon.","date":"2014","source":"Mycotoxin research","url":"https://pubmed.ncbi.nlm.nih.gov/24619360","citation_count":37,"is_preprint":false},{"pmid":"25659824","id":"PMC_25659824","title":"Genetic engineering of Geobacillus spp.","date":"2015","source":"Journal of microbiological methods","url":"https://pubmed.ncbi.nlm.nih.gov/25659824","citation_count":36,"is_preprint":false},{"pmid":"29870549","id":"PMC_29870549","title":"Molecular detection of Bartonella spp. and Rickettsia spp. in bat ectoparasites in Brazil.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29870549","citation_count":36,"is_preprint":false},{"pmid":"27498193","id":"PMC_27498193","title":"Characterization of Roseomonas and Nocardioides spp. for arsenic transformation.","date":"2016","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/27498193","citation_count":36,"is_preprint":false},{"pmid":"32724088","id":"PMC_32724088","title":"Ehrlichia spp. and Anaplasma spp. in Xenarthra mammals from Brazil, with evidence of novel 'Candidatus Anaplasma spp.'.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32724088","citation_count":34,"is_preprint":false},{"pmid":"34293909","id":"PMC_34293909","title":"Biocontrol Activity of Bacillus spp. and Pseudomonas spp. Against Botrytis cinerea and Other Cannabis Fungal Pathogens.","date":"2022","source":"Phytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/34293909","citation_count":31,"is_preprint":false},{"pmid":"29502181","id":"PMC_29502181","title":"Streptomyces spp. in the biocatalysis toolbox.","date":"2018","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/29502181","citation_count":30,"is_preprint":false},{"pmid":"15942758","id":"PMC_15942758","title":"Hessian fly resistance gene H13 is mapped to a distal cluster of resistance genes in chromosome 6DS of wheat.","date":"2005","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/15942758","citation_count":30,"is_preprint":false},{"pmid":"26961274","id":"PMC_26961274","title":"Serological and molecular investigation of Ehrlichia spp. and Anaplasma spp. in ticks and blood of dogs, in the Thrace Region of Turkey.","date":"2016","source":"Ticks and tick-borne diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26961274","citation_count":30,"is_preprint":false},{"pmid":"28198167","id":"PMC_28198167","title":"Signal Peptide Peptidase, Encoded by HM13, Contributes to Tumor Progression by Affecting EGFRvIII Secretion Profiles in Glioblastoma.","date":"2017","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28198167","citation_count":29,"is_preprint":false},{"pmid":"20420533","id":"PMC_20420533","title":"Coexistence of Borrelia spp. and Babesia spp. in Ixodes ricinus ticks in Middle Germany.","date":"2010","source":"Vector borne and zoonotic diseases (Larchmont, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20420533","citation_count":29,"is_preprint":false},{"pmid":"26185068","id":"PMC_26185068","title":"Interactions of Vibrio spp. with Zooplankton.","date":"2015","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/26185068","citation_count":27,"is_preprint":false},{"pmid":"29554923","id":"PMC_29554923","title":"A survey of Babesia spp. and Hepatozoon spp. in wild canids in Israel.","date":"2018","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/29554923","citation_count":27,"is_preprint":false},{"pmid":"16265894","id":"PMC_16265894","title":"The plastid of Plasmodium spp.: a target for inhibitors.","date":"2005","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16265894","citation_count":27,"is_preprint":false},{"pmid":"29145396","id":"PMC_29145396","title":"Detection of relapsing fever Borrelia spp., Bartonella spp. and Anaplasmataceae bacteria in argasid ticks in Algeria.","date":"2017","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29145396","citation_count":27,"is_preprint":false},{"pmid":"28096822","id":"PMC_28096822","title":"Molecular Detection of Anaplasma spp. and Ehrlichia spp. in Ruminants from Twelve Provinces of China.","date":"2016","source":"The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale","url":"https://pubmed.ncbi.nlm.nih.gov/28096822","citation_count":26,"is_preprint":false},{"pmid":"27084487","id":"PMC_27084487","title":"Identification and genotyping of Giardia spp. and Cryptosporidium spp. isolates in aquatic birds in the Salburua wetlands, Álava, Northern Spain.","date":"2016","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/27084487","citation_count":26,"is_preprint":false},{"pmid":"34521455","id":"PMC_34521455","title":"Hyalomma spp. ticks and associated Anaplasma spp. and Ehrlichia spp. on the Iran-Pakistan border.","date":"2021","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/34521455","citation_count":24,"is_preprint":false},{"pmid":"12719012","id":"PMC_12719012","title":"Prevalence of Giardia spp. and Cryptosporidium spp. on dairy farms in southeastern New York state.","date":"2003","source":"Preventive veterinary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12719012","citation_count":23,"is_preprint":false},{"pmid":"14741365","id":"PMC_14741365","title":"Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein.","date":"2004","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/14741365","citation_count":22,"is_preprint":false},{"pmid":"23760233","id":"PMC_23760233","title":"Structure and receptor binding specificity of hemagglutinin H13 from avian influenza A virus H13N6.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23760233","citation_count":22,"is_preprint":false},{"pmid":"22650361","id":"PMC_22650361","title":"Genome and proteome analysis of 7-7-1, a flagellotropic phage infecting Agrobacterium sp H13-3.","date":"2012","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/22650361","citation_count":22,"is_preprint":false},{"pmid":"32724945","id":"PMC_32724945","title":"Protein glycosylation in Leishmania spp.","date":"2020","source":"Molecular omics","url":"https://pubmed.ncbi.nlm.nih.gov/32724945","citation_count":21,"is_preprint":false},{"pmid":"32321814","id":"PMC_32321814","title":"Phylogeography and Antigenic Diversity of Low-Pathogenic Avian Influenza H13 and H16 Viruses.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32321814","citation_count":21,"is_preprint":false},{"pmid":"34493783","id":"PMC_34493783","title":"Porphyromonas spp., Fusobacterium spp., and Bacteroides spp. dominate microbiota in the course of macropod progressive periodontal disease.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34493783","citation_count":21,"is_preprint":false},{"pmid":"28918538","id":"PMC_28918538","title":"Genetic Manipulation of Borrelia Spp.","date":"2018","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28918538","citation_count":20,"is_preprint":false},{"pmid":"21557057","id":"PMC_21557057","title":"Adhesins of Bartonella spp.","date":"2011","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/21557057","citation_count":20,"is_preprint":false},{"pmid":"33244079","id":"PMC_33244079","title":"Antifungal activity of Xenorhabdus spp. and Photorhabdus spp. against the soybean pathogenic Sclerotinia sclerotiorum.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33244079","citation_count":20,"is_preprint":false},{"pmid":"31079344","id":"PMC_31079344","title":"Candida spp. and phagocytosis: multiple evasion mechanisms.","date":"2019","source":"Antonie van Leeuwenhoek","url":"https://pubmed.ncbi.nlm.nih.gov/31079344","citation_count":19,"is_preprint":false},{"pmid":"36153332","id":"PMC_36153332","title":"Histocompatibility Minor 13 (HM13), targeted by miR-760, exerts oncogenic role in breast cancer by suppressing autophagy and activating PI3K-AKT-mTOR pathway.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36153332","citation_count":19,"is_preprint":false},{"pmid":"22555616","id":"PMC_22555616","title":"The isoprenoid-precursor dependence of Plasmodium spp.","date":"2012","source":"Natural product reports","url":"https://pubmed.ncbi.nlm.nih.gov/22555616","citation_count":19,"is_preprint":false},{"pmid":"33195501","id":"PMC_33195501","title":"Molecular Detection and Identification of Babesia spp., Theileria spp., and Anaplasma spp. in Sheep From Border Regions, Northwestern China.","date":"2020","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/33195501","citation_count":19,"is_preprint":false},{"pmid":"17153920","id":"PMC_17153920","title":"Targeted gene mutation in Phytophthora spp.","date":"2006","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/17153920","citation_count":18,"is_preprint":false},{"pmid":"33356057","id":"PMC_33356057","title":"Occurrence of Mycobacterium spp. in ornamental fish.","date":"2019","source":"Annals of agricultural and environmental medicine : AAEM","url":"https://pubmed.ncbi.nlm.nih.gov/33356057","citation_count":18,"is_preprint":false},{"pmid":"25526778","id":"PMC_25526778","title":"Differential identification of Sporothrix spp. and Leishmania spp. by conventional PCR and qPCR in multiplex format.","date":"2014","source":"Medical mycology","url":"https://pubmed.ncbi.nlm.nih.gov/25526778","citation_count":18,"is_preprint":false},{"pmid":"28452684","id":"PMC_28452684","title":"Dynamic interactions of Plasmodium spp. with vascular endothelium.","date":"2016","source":"Tissue barriers","url":"https://pubmed.ncbi.nlm.nih.gov/28452684","citation_count":17,"is_preprint":false},{"pmid":"28657860","id":"PMC_28657860","title":"PREVALENCE OF BABESIA SPP., EHRLICHIA SPP., AND TICK INFESTATIONS IN OKLAHOMA BLACK BEARS (URSUS AMERICANUS).","date":"2017","source":"Journal of wildlife diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28657860","citation_count":17,"is_preprint":false},{"pmid":"31152017","id":"PMC_31152017","title":"Stable Transformation of the Actinobacteria Frankia spp.","date":"2019","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31152017","citation_count":17,"is_preprint":false},{"pmid":"30560519","id":"PMC_30560519","title":"Molecular characterization of South Indian field isolates of bovine Babesia spp. and Anaplasma spp.","date":"2018","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/30560519","citation_count":17,"is_preprint":false},{"pmid":"29914659","id":"PMC_29914659","title":"Microbial Source Tracking of Cronobacter spp.","date":"2018","source":"Advances in applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29914659","citation_count":17,"is_preprint":false},{"pmid":"37080785","id":"PMC_37080785","title":"Strain diversity and infection durations of Staphylococcus spp. and Streptococcus spp. causing intramammary infections in dairy cows.","date":"2023","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/37080785","citation_count":15,"is_preprint":false},{"pmid":"26291147","id":"PMC_26291147","title":"Occurrence of Cryptosporidium spp. and Giardia spp. in a public water-treatment system, Paraná, Southern Brazil.","date":"2015","source":"Revista brasileira de parasitologia veterinaria = Brazilian journal of veterinary parasitology : Orgao Oficial do Colegio Brasileiro de Parasitologia Veterinaria","url":"https://pubmed.ncbi.nlm.nih.gov/26291147","citation_count":15,"is_preprint":false},{"pmid":"35715844","id":"PMC_35715844","title":"Livestock infected with Leishmania spp. in southern Iran.","date":"2022","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/35715844","citation_count":15,"is_preprint":false},{"pmid":"34822520","id":"PMC_34822520","title":"Surface Glucan Structures in Aeromonas spp.","date":"2021","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/34822520","citation_count":14,"is_preprint":false},{"pmid":"21054656","id":"PMC_21054656","title":"Helicobacter spp. other than Helicobacter pylori.","date":"2010","source":"Helicobacter","url":"https://pubmed.ncbi.nlm.nih.gov/21054656","citation_count":14,"is_preprint":false},{"pmid":"32077037","id":"PMC_32077037","title":"Molecular Survey and Genetic Diversity of Babesia spp. and Theileria spp. in Cattle in Gansu Province, China.","date":"2020","source":"Acta parasitologica","url":"https://pubmed.ncbi.nlm.nih.gov/32077037","citation_count":14,"is_preprint":false},{"pmid":"31551069","id":"PMC_31551069","title":"Borrelia spp. in small mammals in Romania.","date":"2019","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/31551069","citation_count":13,"is_preprint":false},{"pmid":"24916958","id":"PMC_24916958","title":"RsaM: a transcriptional regulator of Burkholderia spp. with novel fold.","date":"2014","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/24916958","citation_count":13,"is_preprint":false},{"pmid":"32506629","id":"PMC_32506629","title":"Sensitivity of Pythium spp. and Phytopythium spp. and tolerance mechanism of Pythium spp. to oxathiapiprolin.","date":"2020","source":"Pest management science","url":"https://pubmed.ncbi.nlm.nih.gov/32506629","citation_count":12,"is_preprint":false},{"pmid":"9276993","id":"PMC_9276993","title":"Eimeria spp. from the chicken: occurrence, identification and genetics.","date":"1997","source":"Acta veterinaria Hungarica","url":"https://pubmed.ncbi.nlm.nih.gov/9276993","citation_count":12,"is_preprint":false},{"pmid":"35973774","id":"PMC_35973774","title":"Bioactivity of mefentrifluconazole against different Fusarium spp.","date":"2022","source":"Pesticide biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35973774","citation_count":12,"is_preprint":false},{"pmid":"36877121","id":"PMC_36877121","title":"Cross-species infection potential of avian influenza H13 viruses isolated from wild aquatic birds to poultry and mammals.","date":"2023","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/36877121","citation_count":12,"is_preprint":false},{"pmid":"29648539","id":"PMC_29648539","title":"Horizontal Gene Transfer in Thermus spp.","date":"2018","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29648539","citation_count":11,"is_preprint":false},{"pmid":"30006543","id":"PMC_30006543","title":"Investigation of Wolbachia spp. and Spiroplasma spp. in Phlebotomus species by molecular methods.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30006543","citation_count":11,"is_preprint":false},{"pmid":"32491136","id":"PMC_32491136","title":"Nutritional assay Pereskia spp.: unconventional vegetable.","date":"2020","source":"Anais da Academia Brasileira de Ciencias","url":"https://pubmed.ncbi.nlm.nih.gov/32491136","citation_count":11,"is_preprint":false},{"pmid":"33622359","id":"PMC_33622359","title":"Multiple mycoviruses identified in Pestalotiopsis spp. from Chinese bayberry.","date":"2021","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/33622359","citation_count":11,"is_preprint":false},{"pmid":"39320166","id":"PMC_39320166","title":"Bartonella spp. in Phlebotominae Sand Flies, Brazil.","date":"2024","source":"Emerging infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39320166","citation_count":11,"is_preprint":false},{"pmid":"34638661","id":"PMC_34638661","title":"Plasmidome of Listeria spp.-The repA-Family Business.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34638661","citation_count":11,"is_preprint":false},{"pmid":"32221942","id":"PMC_32221942","title":"Isolation of Extracellular Vesicles from Leishmania spp.","date":"2020","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32221942","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49583,"output_tokens":1503,"usd":0.085647,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8225,"output_tokens":2053,"usd":0.046225,"stage2_stop_reason":"end_turn"},"total_usd":0.131872,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"C. elegans imp-2 (ortholog of human HM13/SPP) is functionally distinct from presenilins: knockdown causes embryonic death and molting defects but does NOT promote Notch (lin-12, glp-1) proteolysis or signaling, placing IMP/SPP outside the presenilin-Notch pathway.\",\n      \"method\": \"C. elegans RNAi knockdown with phenotypic readout (embryonic lethality, molting defect); genetic epistasis with lin-12/glp-1 Notch pathway\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined phenotype plus epistasis analysis, single lab but two orthogonal approaches (phenotype + pathway placement)\",\n      \"pmids\": [\"15469912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The imp-2/HM13 developmental function in C. elegans is linked to a lipid/lipoprotein receptor-mediated pathway: the molting defect caused by Ce-imp-2 depletion was mimicked by cholesterol depletion or disruption of Ce-lrp-1 (megalin/LRP ortholog) and partially suppressed by a Ce-lrp-1 derivative, placing IMP/SPP upstream of or parallel to the LRP cholesterol/lipoprotein endocytosis pathway.\",\n      \"method\": \"Genetic epistasis in C. elegans: RNAi of Ce-imp-2 combined with cholesterol depletion and Ce-lrp-1 manipulation; partial rescue by Ce-lrp-1 derivative expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with rescue experiment, single lab, multiple genetic conditions tested\",\n      \"pmids\": [\"15469912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human HM13/IMP1 (SPP) possesses endoproteolytic activity and cleaves the presenilin-1 holoprotein within its transmembrane domain in cultured cells; mutation of evolutionarily invariant residues (putative catalytic aspartates) in hIMP1 abolishes this cleavage, and specific gamma-secretase inhibitors also block the activity, demonstrating that HM13/SPP is a bi-aspartic intramembrane protease capable of cleaving multipass transmembrane substrates.\",\n      \"method\": \"Co-expression in cultured cells; active-site mutagenesis of invariant aspartate residues; pharmacological inhibition with gamma-secretase inhibitors; endoproteolysis assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in-cell enzymatic activity assay combined with active-site mutagenesis and pharmacological inhibition, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"14741365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HM13/SPP promotes secretion of cytokines from EGFRvIII-expressing glioblastoma cells: SPP knockdown significantly reduced cytokine levels in EGFRvIII conditioned media and attenuated intracellular maturation of TGF-β1, indicating SPP acts in the endoplasmic reticulum to facilitate processing and secretion of cytokines, thereby promoting tumor progression in vivo.\",\n      \"method\": \"siRNA knockdown of HM13/SPP in glioblastoma cells; human cytokine antibody array; intracellular maturation tracking of TGF-β1; mouse xenograft tumor model\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular readout (cytokine secretion profiling) plus in vivo validation, single lab\",\n      \"pmids\": [\"28198167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HM13 knockdown in breast cancer cells activates autophagy by inducing endoplasmic reticulum (ER) stress and inhibits the PI3K-AKT-mTOR signaling pathway, placing HM13 as a suppressor of autophagy acting through the PI3K-AKT-mTOR axis in the ER context.\",\n      \"method\": \"siRNA knockdown of HM13 in breast cancer cells; autophagy assays; ER stress markers; PI3K-AKT-mTOR pathway activity assays; xenograft tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple pathway readouts and in vivo confirmation, single lab\",\n      \"pmids\": [\"36153332\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HM13 (SPP/IMP1) is a bi-aspartic intramembrane protease resident in the endoplasmic reticulum that cleaves type-I and multipass transmembrane substrates (including presenilin-1 holoprotein) via catalytic aspartate residues; it is functionally distinct from presenilins in that it does not promote Notch signaling, instead acting in a pathway linked to lipid/lipoprotein receptor-mediated endocytosis during development, and in cancer contexts it facilitates cytokine secretion and suppresses autophagy by modulating ER stress and the PI3K-AKT-mTOR pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HM13 (SPP/IMP1) is a bi-aspartic intramembrane protease of the endoplasmic reticulum that cleaves transmembrane substrates through invariant catalytic aspartate residues, demonstrated by its endoproteolysis of the presenilin-1 holoprotein within its transmembrane domain and the loss of this activity upon active-site mutagenesis or gamma-secretase inhibitor treatment [#2]. Despite the shared catalytic chemistry, HM13 is functionally distinct from presenilins: its ortholog does not promote Notch proteolysis or signaling but is instead required for development, where loss causes embryonic lethality and molting defects linked to a lipid/lipoprotein receptor (LRP/megalin) endocytosis pathway [#0, #1]. In cancer contexts HM13 operates in the ER to facilitate intracellular maturation and secretion of cytokines including TGF-\\u03b21, promoting tumor progression [#3], and to suppress autophagy by restraining ER stress and sustaining PI3K-AKT-mTOR signaling [#4]. The full catalog of physiological transmembrane substrates beyond presenilin-1 has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that the IMP/SPP family is mechanistically separable from presenilins, answering whether this protease functions within the canonical presenilin-Notch pathway.\",\n      \"evidence\": \"C. elegans imp-2 RNAi knockdown with phenotypic readout and genetic epistasis against lin-12/glp-1 Notch signaling\",\n      \"pmids\": [\"15469912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the protease substrate responsible for the developmental phenotype\", \"Notch independence shown genetically but not biochemically in human cells\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed HM13's developmental role within a lipid/lipoprotein receptor endocytosis pathway, providing the first physiological context for its in vivo function.\",\n      \"evidence\": \"C. elegans epistasis combining imp-2 RNAi with cholesterol depletion and Ce-lrp-1 manipulation, with partial rescue by an Ce-lrp-1 derivative\",\n      \"pmids\": [\"15469912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HM13 acts directly on LRP/megalin or upstream is unresolved\", \"No molecular substrate linking the protease activity to cholesterol/lipoprotein endocytosis identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined HM13 as a bi-aspartic intramembrane protease, answering the core question of its catalytic mechanism and substrate range.\",\n      \"evidence\": \"Co-expression endoproteolysis assay of presenilin-1 holoprotein in cultured cells with active-site aspartate mutagenesis and gamma-secretase inhibitor blockade\",\n      \"pmids\": [\"14741365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate repertoire beyond presenilin-1 not defined\", \"No structural model of the catalytic mechanism\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected HM13's ER protease activity to a secretory function, showing it facilitates cytokine processing and release to drive tumor progression.\",\n      \"evidence\": \"siRNA knockdown in EGFRvIII glioblastoma cells with cytokine antibody array, TGF-\\u03b21 maturation tracking, and mouse xenograft\",\n      \"pmids\": [\"28198167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cytokine maturation requires HM13 proteolytic activity or a non-catalytic role is unclear\", \"Direct substrate cleaved by HM13 in the secretory pathway not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified HM13 as a suppressor of autophagy, linking its ER function to the PI3K-AKT-mTOR axis and ER stress control.\",\n      \"evidence\": \"siRNA knockdown in breast cancer cells with autophagy and ER stress markers, PI3K-AKT-mTOR activity assays, and xenograft model\",\n      \"pmids\": [\"36153332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting HM13 protease activity to ER stress and mTOR signaling not defined\", \"Direct molecular intermediate between HM13 and the PI3K-AKT-mTOR pathway unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological transmembrane substrates of HM13 and the mechanism linking its intramembrane proteolysis to cytokine secretion, autophagy, and lipoprotein endocytosis remain unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous substrate beyond presenilin-1 characterized\", \"Catalytic requirement for the cancer-associated phenotypes not established\", \"No structural basis for substrate selection\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PSEN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}