HM13

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.

1. 2004 Medium

   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

   PMID:15469912

   Open questions at the time

   • Did not identify the protease substrate responsible for the developmental phenotype
   • Notch independence shown genetically but not biochemically in human cells
2. 2004 Medium

   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

   PMID:15469912

   Open questions at the time

   • Whether HM13 acts directly on LRP/megalin or upstream is unresolved
   • No molecular substrate linking the protease activity to cholesterol/lipoprotein endocytosis identified
3. 2004 High

   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

   PMID:14741365

   Open questions at the time

   • Physiological substrate repertoire beyond presenilin-1 not defined
   • No structural model of the catalytic mechanism
4. 2017 Medium

   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

   PMID:28198167

   Open questions at the time

   • 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
5. 2022 Medium

   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

   PMID:36153332

   Open questions at the time

   • 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

• The physiological transmembrane substrates of HM13 and the mechanism linking its intramembrane proteolysis to cytokine secretion, autophagy, and lipoprotein endocytosis remain unresolved.
• No endogenous substrate beyond presenilin-1 characterized
• Catalytic requirement for the cancer-associated phenotypes not established
• No structural basis for substrate selection