. CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7499-504. PubMed.

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  1. The recent manuscript by Zhou et al. clearly shows that CD147 co-purifies with the γ-secretase complex. However, the claim that it is a novel regulatory subunit of the complex is likely to be debated. CD147 is a type 1 membrane protein that is in the IgG superfamily. Its ectodomain can be shed, and its juxtamembrane region (QAIITLRVRSHLAALWPFLGIVAEVLVLVTIIFIYEKRRK; transmembrane region in bold) resembles many known substrates that are cleaved by γ-secretase. As APP carboxyl-terminal fragments have been shown to co-purify with γ-secretase, there is precedent that substrate can associate with the complex. This has led to the proposal by Michael Wolfe and colleagues that γ-secretase has a docking site that is distinct from its active site. CD147 as a γ-secretase substrate can explain most of the observations in the manuscript. CD147 might compete for cleavage of other substrates; thus, downregulating CD147 could increase cleavage by other substrates. Indeed, under certain circumstances, γ-secretase substrates can compete for cleavage. In any case, I think experiments to examine whether CD147 is another γ-substrate are warranted. It is perplexing that what appears to be full-length CD147 does co-purify with the complex. Perhaps in its uncleaved form, it can bind the complex at the docking site but not get cleaved.

  2. This interesting report by Zhou et al. suggests that intramembranous cleavage of APP by γ-secretase is negatively regulated by a cell surface type I membrane protein, termed CD147/basigin/EMMPRIN, which belongs to the immunoglobulin superfamily. The authors identified CD147 as a subunit of the γ-secretase complex, based on its coelution with native γ-secretase complex during chromatographic purification from HeLa cells. Two important features of CD147 indicate that it is a regulatory subunit, and not one of the core components (such as PS1, nicastrin, APH-1 and PEN2), of the γ-secretase complex. First, siRNA-mediated CD147 knockdown studies using CHO cells caused a modest increase in the levels of secreted Aβ40 and Aβ42 peptides. Second, CD147 depletion had no effect on the stability of the γ-secretase complex components. In contrast to the behavior of CD147, absence or depletion of any one of the core components destabilizes the other mature components and leads to invariable loss of Aβ production.

    While the findings in this report are intriguing, certain aspects of the study will definitely raise concerns. This is the first study to use FOS-CHOLINE-12 to solubilize the γ-secretase complex. Specifics on the detergent concentration and solubilization conditions employed to rule out potential micelle formation are not detailed in the report. Since CD147 is an abundant membrane protein, the use of additional detergents and cross-linking agents are critical to validate the interaction studies. It is still an open question whether anti-CD147 antibody-captured complex, isolated from FOS-CHOLINE-12 lysates diluted below the critical micelle-forming concentration of detergent, displays γ-secretase activity. With the lack of information on the levels of APP C-terminal fragments in CD147 knockdown cells, the readers are left to speculate whether loss of CD147 indeed influenced catalysis of APP C-terminal fragments at the γ-secretase cleavage site. The potential function of CD147 in secretion/release of matrix metalloproteinase (MMP) raises the possibility that CD147 may indirectly affect Aβ secretion by influencing the trafficking or localization of APP and/or the components of PS1-complex. In this context, direct measure of the γ-secretase activity using established in vitro assays will be highly informative. As the spectrum of γ-secretase widens, it is not unlikely that CD147 itself may be a substrate for intramembranous proteolysis by the γ-secretase. Should this be the case, it wouldn’t be hard to envision an increase in Aβ with a reduction in CD147, a competitive substrate. It is also critical to validate the cell culture data in other biological systems (e.g., in the roundworm C. elegans and fruit flies) and investigate Aβ burden in APP transgenic mice in CD147 -/- background or with overexpression of CD147.

    Given the heightened interest in the biology of γ-secretase, several of these issues will undoubtedly be addressed in the coming months and exciting insights will soon begin to unravel. Other questions relating to the predominant cell surface residence of CD147, however, will take substantial effort to answer: Does CD147 assemble with nascent γ-secretase components in the ER and escort them to their final destination (as is the case with the trafficking of MCT1 to the plasma membrane)? Is the influence of CD147 limited to a small pool of γ-secretase at the plasma membrane? Does loss of CD147 affect γ-secretase cleavage of additional substrates, especially the ones that are more abundant than APP at the plasma membrane (e.g., Notch)?

    CD147 is a molecule of complex biology. It regulates multiple biological processes, notably neural-glial interaction in the developing retina, activation of matrix metalloproteases, and the regulation of immune response. CD147-/- mice are associated with other defects such as embryonic lethality around the time of implantation, postnatal lethality, reduced body weight, and pathology in lung and liver in certain genetic backgrounds, but not in others. Only two fully penetrant phenotypes, namely retinal degeneration and sterility, are associated with CD147-/- mice (Chen et al., 2004). Absence of somite segmentation defects in CD147-/- embryos suggests that loss of CD147 expression does not adversely affect γ-secretase processing of Notch during mammalian development. In this regard, CD147 might hold important clues regarding the differential recognition of substrates by the γ-secretase complex, one that is a central theme in potential therapeutic targeting of the γ-secretase.

    References:

    . Effects of flanking genes on the phenotypes of mice deficient in basigin/CD147. Biochem Biophys Res Commun. 2004 Nov 5;324(1):147-53. PubMed.

  3. Malaguarnera et al. report a possible link with Helicobacter pylori and Alzheimer disease.

    Might we suspect molecular mimicry at play here? Helicobacter pylori may express the Lewis X antigen. Would you expect that an immune reaction may also be directed to CD147?

    Fan et al. report that the expression of basigin (CD147) correlates with the expression of LeX antigen and fucosyltransferase IV.

    Is it a coincidence that amyloidosis may occur during the course of a Schistosoma mansoni infection? An immune response is raised against LeX during this infection.

    Gray et al. report an association with cerebral amyloid angiopathy and granulomatous angiitis, and suggest that granulomatous angiitis may represent a foreign-body reaction to A4 amyloid deposition. Would you expect neuroschistosomiasis may be associated with amyloid deposits which have occurred due to an antigenic response to LeX and subsequently reduced CD147?

    References:

    . Helicobacter pylori and Alzheimer's disease: a possible link. Eur J Intern Med. 2004 10;15(6):381-386. PubMed.

    . Embigin/basigin subgroup of the immunoglobulin superfamily: different modes of expression during mouse embryogenesis and correlated expression with carbohydrate antigenic markers. Dev Growth Differ. 1998 Jun;40(3):277-86. PubMed.

    . Discrimination between the anti-monomeric and the anti-multimeric Lewis X response in murine schistosomiasis. Microbes Infect. 2004 Nov;6(13):1125-32. PubMed.

    . Cerebral amyloid angiopathy and granulomatous angiitis: immunohistochemical study using antibodies to the Alzheimer A4 peptide. Hum Pathol. 1990 Dec;21(12):1290-3. PubMed.

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