Cheng SB, Ferland P, Webster P, Bearer EL.
Herpes simplex virus dances with amyloid precursor protein while exiting the cell.
PLoS One. 2011;6(3):e17966.
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In this report, Cheng and coworkers describe an interaction between herpes simplex virus type 1 (HSV1) and amyloid precursor protein (APP) that alters the cellular distribution and trafficking of APP. Impressively, they have used a variety of methods, including fixed and live-cell fluorescence microscopy and immunoelectron microscopy, to demonstrate colocalization between HSV1 and APP. These results are interesting, given resurgence in interest surrounding HSV1 as a putative environmental risk factor for AD.
The authors have nicely demonstrated that HSV1 and APP colocalize, and that this interaction increases APP expression and alters APP distribution within cells. Yet, beyond this, it is unclear whether the reported interaction with APP is 1) specific to HSV1 versus other viruses, or 2) has functional implications for APP or HSV1 biology. Regarding the former, perhaps high-level infection of cells (at multiplicity of infection of 10, which was used in this report) with other viruses (or even herpesviruses other than HSV1) may also produce interactions with APP and/or other APP-like glycoproteins. For me, though, the key question is whether these interactions alter APP or HSV1 biology. For example, does knocking down APP as the authors have done in this paper alter HSV1 infectivity (by plaque assay)? Does HSV1 versus mock infection impact amyloidogenic APP metabolism? Finally, that APP is exclusively present within the trans-Golgi network in the authors’ wild-type, mock-infected cells is curious, given decades of work in neuronal cells showing membranous/endosomal/lysosomal localization of APP. Does APP trafficking behave differently in the authors’ epithelial cell culture system compared with neuronal models? In my view, these are the sorts of penetrating biological questions that should be addressed in future studies.
Whether abnormal axonal transport is a cause or a consequence of the neuronal pathology in Alzheimer’s disease (AD) is largely debated (1). The recent paper from the Bearer lab suggests that perturbed axonal transport of amyloid-β precursor protein (APP) could be at the core of the pathogenic process in AD. As proposed by the authors, the disruption of the normal transport and—consequently—localization of APP could result from infection with herpes simplex virus (HSV). More specifically, by using APP—a potential anchor for the microtubule motor, kinesin-1—to achieve its own intracellular transport needs required for infectivity, the virus also modifies the normal transport route of APP, and thus its processing and function. How these events lead to the neuronal pathology and the lesions that characterize AD is not addressed, but the findings open the door for speculative thoughts. There are, however, some defined questions that this study raises. For example, why are APP levels upregulated to considerable high extent upon HSV infection? Is APP kept away from the compartments where its processing and degradation normally occur? Is all intracellular trafficking perturbed, not only that of APP? It should be, since the reorganization—or disorganization—of the microtubule cytoskeleton, as revealed by the provided images, appears to be global. What is the consequence of altered trafficking of APP? Does it have an effect on processing, on the intracellular accumulation and secretion of APP-derived fragments, including the amyloid-β peptide? Or does it simply alter APP’s yet to be identified function, by mislocalization?
The interpretation of the data from this study relies on the assumption that APP is involved in the recruitment of the kinesin-1 motor to the cargo vesicle that is hijacked by the virus particles; this highly debated aspect (2) is not addressed in this paper. The notion that at least part of APP could serve—directly or indirectly—as an anchor for kinesin-1 (3-5) provides support for such an interpretation. Moreover, even if only a small fraction of APP normally serves such a role, viral infection could lead to post-translational modifications (e.g., phosphorylation, prolyl isomerisation, and O-glycosylation) in the cytoplasmic domain of APP that could either impair or enhance its interaction with motor containing protein complexes. Phosphorylation of APP at Thr668 is known to facilitate recruitment of kinesin-1 via the JNK-interacting protein-1 (JIP-1) (5,6). In addition, phosphorylation of threonine and tyrosine residues in APP appears to be a general mechanism for regulating its interaction with known binding partners (7). In this context, of note is that the cytoplasmic O-linked N-acetylglucosamine O-GlcNAc transferase capable of adding N-acetylglucosamine to APP (8) also targets the transcriptional co-regulator, HCF-1 (9), a host-cell factor implicated in HSV infection. Could the two events be related? It is too early to speculate. In any case, the fact that the outgoing capsids travel with APP is certainly relevant for both HSV infection and AD, even if it turns out that—in this case—APP is not the anchor that recruits the motor to the vesicle. The HSV-APP connection is still there, although more mysterious.
In his comment to this paper, Terrence Town points out that the authors find APP almost exclusively present within the trans-Golgi network (TGN), and not in endosomes. However, in our studies, we found it difficult to determine the site of residence of APP at light microscopy level based exclusively on colocalization with organelle markers. This is because the TGN, the endosomal recycling compartment, the pericentrosomal periciliary compartment—to give just a few examples—are all localized to overlapping regions, and often share “marker” proteins. Thus, part of the detected APP in this study could actually be localized to some other exocytic-endocytic compartments, in addition to TGN.
Certainly, this interesting and informative study adds to the fascinating, but far from being solved, mystery of what causes, or predisposes to, AD.
Muresan V, Muresan Z.
Is abnormal axonal transport a cause, a contributing factor or a consequence of the neuronal pathology in Alzheimer's disease?.
Future Neurol. 2009 Nov 1;4(6):761-773.
Lazarov O, Morfini GA, Lee EB, Farah MH, Szodorai A, DeBoer SR, Koliatsos VE, Kins S, Lee VM, Wong PC, Price DL, Brady ST, Sisodia SS.
Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited.
J Neurosci. 2005 Mar 2;25(9):2386-95.
Inomata H, Nakamura Y, Hayakawa A, Takata H, Suzuki T, Miyazawa K, Kitamura N.
A scaffold protein JIP-1b enhances amyloid precursor protein phosphorylation by JNK and its association with kinesin light chain 1.
J Biol Chem. 2003 Jun 20;278(25):22946-55.
Matsuda S, Matsuda Y, D'Adamio L.
Amyloid beta protein precursor (AbetaPP), but not AbetaPP-like protein 2, is bridged to the kinesin light chain by the scaffold protein JNK-interacting protein 1.
J Biol Chem. 2003 Oct 3;278(40):38601-6.
Muresan Z, Muresan V.
Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1.
J Cell Biol. 2005 Nov 21;171(4):615-25.
Muresan Z, Muresan V.
c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein.
J Neurosci. 2005 Apr 13;25(15):3741-51.
Tamayev R, Zhou D, D'Adamio L.
The interactome of the amyloid beta precursor protein family members is shaped by phosphorylation of their intracellular domains.
Mol Neurodegener. 2009;4:28.
Griffith LS, Mathes M, Schmitz B.
Beta-amyloid precursor protein is modified with O-linked N-acetylglucosamine.
J Neurosci Res. 1995 Jun 1;41(2):270-8.
Capotosti F, Guernier S, Lammers F, Waridel P, Cai Y, Jin J, Conaway JW, Conaway RC, Herr W.
O-GlcNAc transferase catalyzes site-specific proteolysis of HCF-1.
Cell. 2011 Feb 4;144(3):376-88.
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