In the January 31 online PNAS, Meir Scheinfeld, Shuji Matsuda, and Luciano D'Adamio of the Albert Einstein College of Medicine in Bronx, New York, show how the carboxyl terminus of AβPP could play a significant role in gene transcription, with implications for neurodegeneration in Alzheimer's disease.
The authors shift our attention to the "other" peptide-the AβPP intracellular domain (AICD)-which slips quietly away after γ-secretase cleaves AβPP, leaving Aβ in the harsh glare of the searchlight. The AICD peptide is less stable and more difficult to detect than its sibling, but recent investigations (beginning with Cao and Sudhof's work, ARF news story) have suggested it could play a role in transcriptional regulation (see also ARF news story; ARF news story; and ARF live discussion). There is even the suggestion from D'Adamio's group that AICD plays a role in apoptosis (Passer et al, 2000; see also related ARF discussion). In the present study, Scheinfeld and colleagues tracked the AICD peptide in its interactions with other proteins, especially the Janus kinase interacting protein (JIP-1), a scaffold protein that binds various elements of the Janus kinase (JNK) cascade. They also explore differences in the way AβPP and its relatives, AβPP-like protein-1 (APLP1) and APLP2, interact with other proteins to help regulate gene activity.
The researchers found that JIP-1 activates transcription in cultured cells transfected with the carboxyl terminus of AβPP. By contrast, other proteins (ShcA, ShcC, NCl) that bind AICD in the same region (the phosphotyrosine binding YENPTY motif) do not activate transcription with this interaction. In addition, the authors showed that individual domains of the protein were insufficient for this activity, and that full-length JIP-1 is required to activate transcription. Similarly, they used point mutations in AβPP to confirm that the gene activation can be traced to JIP-1 binding to AβPP. Scheinfeld and colleagues also confirm that AβPP must be cleaved by the PS-1/γ-secretase complex before this JIP-1-mediated transcription can occur. The activity is blocked by γ-secretase inhibitors and in cells where PS-1 activity is blocked.
Similar to JIP-1, the protein Fe65 interacts with AβPP to regulate transcription. It does this by moving into the nucleus together with AICD, and this process is regulated by the protein Tip60 (see also Rosenfeld et al., 2002). Importantly, Scheinfeld and colleagues report, JIP-1 is not translocated to the nucleus in its AICD-related transcriptional activities, nor is it dependent on Tip60.
Finally, the researchers determined that JIP-1-related transcriptional activation is something AβPP's cousins APLP-1 and APLP-2 (via their AβPP-like intracellular domains, or ALIDs) are not capable of. These data, write the authors, may help to explain why AβPP and the APLPs are apparently interchangeable for some functions (such as normal development), but not for others. "Considering that the AICD fragment is produced by processing, and its ability to induce gene activation with JIP-1 is not shared with the ALIDs, it is possible that the functional consequences of the AICD/JIP-1 interaction, including its transcription-modulating properties, may also be important in the pathology of AD," the authors conclude.—Hakon Heimer
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- Passer B, Pellegrini L, Russo C, Siegel RM, Lenardo MJ, Schettini G, Bachmann M, Tabaton M, D'Adamio L. Generation of an apoptotic intracellular peptide by gamma-secretase cleavage of Alzheimer's amyloid beta protein precursor. J Alzheimers Dis. 2000 Nov;2(3-4):289-301. PubMed.
- Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. Cell. 2002 Jul 12;110(1):55-67. PubMed.
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- Scheinfeld MH, Matsuda S, D'Adamio L. JNK-interacting protein-1 promotes transcription of A beta protein precursor but not A beta precursor-like proteins, mechanistically different than Fe65. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1729-34. PubMed.