SUMO-Wrestling with APP?
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In the January 7 PNAS, researchers from the biopharmaceutical company Scios Inc. reported that sumoylation, the covalent modification of lysine residues by small ubiquitin-like modifier (SUMO) proteins, has a dramatic impact on amyloid β production.
Working with principle investigator Barbara Cordell, first author Yonghong Li et al. discovered the sumoylation effect in a random screen of plasmids that can affect Aβ processing when transfected into human cells expressing Aβ precursor protein (AβPP). Of the roughly 100,000 plasmids harboring cDNA from human fetal brain tissue, one downregulated the expression of the N-terminal fragments produced by β-site cleavage of AβPP (β-NTF), and upregulated production of α-NTFs, the fragments produced by cleavage at the α-site. This plasmid turned out to code for SUMO-3.
When Li et al. further investigated this effect, they found a dose-response relationship between SUMO-3 and AβPP processing. At the highest doses of plasmid, Aβ production shrank by 25 percent, and there were concomitant increases and decreases in levels of α-NTF and β-NTF. In addition, dominant-negative mutants of SUMO-3 led to increased β-NTF and Aβ production, suggesting that endogenous SUMO-3 is involved in keeping these levels low.
While the connection between sumoylation and Aβ production is intriguing, this report raises many questions. For example, what substrates of SUMO-3 are involved in the regulation of AβPP processing? The authors show that neither the precursor, nor the enzyme responsible for the β-site cleavage (BACE), is sumoylated. They also show that SUMO-3 is present in hippocampal neurons and they hint at preliminary observations suggesting altered expression in Alzheimer's brains versus controls. To our knowledge, this is the first time sumoylation has been implicated directly in Alzheimer’s disease, however, there are prior reports suggesting that this form of post-translational protein modification plays a role in polyglutamine repeat diseases (Ueda et al., 2002; Chan et al., 2002).—Tom Fagan
References
Paper Citations
- Ueda H, Goto J, Hashida H, Lin X, Oyanagi K, Kawano H, Zoghbi HY, Kanazawa I, Okazawa H. Enhanced SUMOylation in polyglutamine diseases. Biochem Biophys Res Commun. 2002 Apr 26;293(1):307-13. PubMed.
- Chan HY, Warrick JM, Andriola I, Merry D, Bonini NM. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet. 2002 Nov 1;11(23):2895-904. PubMed.
Further Reading
No Available Further Reading
Primary Papers
- Li Y, Wang H, Wang S, Quon D, Liu YW, Cordell B. Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):259-64. PubMed.
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Comments
Boston University School of Medicine
The findings by Li et al. on the regulation of APP processing by sumoylation indeed bring a new perspective to the field of AD research. Although the authors documented a lack of direct sumoylation of APP and BACE, they have demonstrated a clear increase of α-NTF (derived from α-secretase cleavage of APP) and a reduction of β-NTF (derived from β-secretase cleavage of APP) when SUMO-3 is overexpressed. When mutant SUMO-3 is overexpressed, all of α-NTF, β-NTF and Aβ are increased. Importantly, overexpressing either wildtype or mutant SUMO-3 leads to increased steady-state levels of APP.
Based on these observations, it will be interesting to search for any effect of sumoylation on α-secretase, which is not discussed in the paper. I would predict an increase of α-secretase activity by sumoylation. Overexpression of wildtype SUMO-3 could lead to enhanced α-secretase, resulting in increased α-NTF levels, reduced β-NTF levels (and subsequently reduced Aβ levels.) On the contrary, overexpression of mutant forms of SUMO-3 may not affect α-secretase activity, and increased levels of α-NTF, β-NTF and Aβ could result simply from increased steady-state levels of APP in these cells.
If the above prediction is correct, several conclusions in the paper might need to be reevaluated, e.g., a positive effect of monosumoylation on Aβ production, an indirect effect of sumoylation on APP processing. Nevertheless, the authors may have already examined the α-secretase and failed to find any effect.
Regarding the physiological relevance of sumoylation to AD pathology, this paper has mentioned a SUMO-3 distribution to the neuronal soma from AD and Down’s syndrome brains, in contrast to both soma and nuclear from nondemented brains. Sumoylation of transcription factors plays an important role in regulating gene expression, and the observations described in this paper can be pursued to explore differential gene expressions during the development of AD pathology.
Boston University School of Medicine
This article presents a novel regulatory mechanism for APP processing. Li et al. observe that increased expression of SUMO-3 increases production of Aβ and reduces production of APPsα. SUMO (small ubiquitin-like modifier) proteins are small peptides that are added to proteins in a manner similar to ubiquitin, unlike ubiquitin however, they do not target proteins for proteasomal degradation. The function of SUMO is not well understood, but in cases where it has been examined SUMO appears to control localization of proteins within the cell, such as targeting to particular organelles or the nucleus. For instance, herpes virus particles appear to form inclusions by manipulating the SUMO system. Consistent with this model, Li and colleagues do not observe a significant effect of SUMO on the turnover of APP. Since little is known about SUMO, Li’s observation opens up a new chapter in the regulation of APP processing and will likely yield new and interesting findings in the upcoming months and years.
Icahn School of Medicine at Mount Sinai
Posttranslational modification of the cytoplasmic tail of APP has emerged as an important mechanism for controlling APP metabolism and Aβ generation. These phenomena can be divided into two basic cellular phenotypes: modifications that regulate the α- and β-secretase pathways in parallel, and others that regulate the two pathways in a reciprocal fashion. In both cases, the molecular basis appears to be alteration of APP trafficking. Some APP-tail-binding proteins appear to promote retention of APP in the ER, slowing APP flux down both to the α and β pathways. The best known means of regulating the α and β pathways in a reciprocal manner is accomplished by activation of signal transduction pathways, such as those mediated by protein kinase C (PKC) and extracellular signal regulated protein kinase (ERK). To date, no "cellular machinery" has been discovered that is capable of transducing changes in cytoplasmic protein phosphorylation into activation or inhibition of intralumenal proteolysis. Accelerated vesicle biogenesis at the trans-Golgi network (TGN) appears to explain at least part of the response to activation of PKC or ERK.
Now, Barbara Cordell and her colleagues have demonstrated that the "regulated cleavage" phenotype can be induced by addition of small ubiquitin-like modifiers to the APP cytoplasmic tail. α cleavage is activated upon "SUMOylation" of APP, and β cleavage is reciprocally reduced. As with PKC and ERK activation, one subcellular mechanism might include the redistribution of "SUMOylated" APP toward the plasma membrane, where α-secretase is encountered. This mechanism does not completely explain the phenomenon unless the sorting machinery at the TGN is operating under limiting substrate conditions. Otherwise, there must also be a separate explanation for how the β pathway is inhibited.
"SUMOylation" joins the growing list of signals that can modulate APP metabolism: acetylcholine, interleukin-1, estrogen, testosterone, insulin, IGF-1. The life cycle of APP is coming to light, revealing an exquisitely fine-tuned balance of competing proteolytic pathways. The relative activity of these competing pathways is governed by the activation state or the hormone responsiveness of the cell. These regulatory factors may contribute to the association of Alzheimer's with disturbances in the levels of gonadal and peptide hormones.
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