Recent studies revealed an emerging role of PML-NBs as coregulatory structures of both type I and type II interferon responses.
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Transcription of PML is strongly upregulated by interferons and p53, causing a significant increase in the number and size of the bodies. While their precise biochemical functions have not been elucidated yet, they have been linked to many aspects of chromatin biology, including transcription, histone modification, repair and recombination, degradation, hence genome maintenance. PML-NBs are highly dynamic structures with respect to mobility, composition, architecture, and function. A diverse set of nuclear proteins have been identified as permanent or transient PML-NB-binding partners. Promyelocytic leukemia nuclear bodies (PML-NBs) are multiprotein complexes with PML as the main building component.
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Indeed, a variety of target genes like GSK3β, IDE, and APP have been proposed to be APP-CT50 dependently regulated. The presence of the histone acetyl transferase (TIP60) and the DNA helicase (BLM) in the complex points to a functional role in essential biological mechanisms such as gene expression, DNA replication/damage/repair or chromatin modification. APP-CT50 is capable to enter the nucleus establishing a protein complex consisting of additional proteins like FE65, TIP60, and BLM. Though, this changes upon interaction with FE65, causing APP-CT50 to fold into a three-dimensional conformation that can be analysed by x-ray crystallography.
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APP-CT, which has been reported to exist in different isoforms with 50aa in length being the most stable one (APP-CT50), indeed is a remarkable protein fragment as it is intrinsically unstructured. The secreted fragment (i) was reported to provoke neurotrophic effects, Aβ (ii) is the main component of amyloidogenic plaques and APP-CT (iii) was suggested to play an important role in a nuclear signal transduction pathway. Amyloidogenic APP processing causes the generation of three fragments: (i) the secreted extracellular domain (sAPPβ), (ii) the β-amyloid peptide (Aβ), and (iii) the APP C-terminal fragment (APP-CT). Increased amyloidogenic processing of the amyloid precursor protein (APP) occurs in sporadic Alzheimer’s disease (AD), in familial AD with mutations in APP or in its processing enzymes, and in trisomy 21 patients. Based on these results we conclude that APP-CT50 signalling to the nucleus takes place in the aged human brain and is involved in the pathophysiology of AD. Notably, human Alzheimer’s disease brains reveal a highly significant reduction of these nuclear aggregates in areas with high plaque load compared to plaque-free areas of the same individual. We further show that the nuclear aggregates of APP-CT50 fragments together with PML and FE65 are present in the aged human brain but not in cerebral organoids differentiated from iPS cells. The PML nuclear body generation is induced and fusion occurs over time depending on APP signalling and STED imaging revealed active gene expression within the complex. APP C-terminal (APP-CT50) complexes co-localize and co-precipitate with p53 and PML. The current study demonstrates that APP signals to the nucleus causing the generation of aggregates consisting of its adapter protein FE65, the histone acetyltransferase TIP60 and the tumour suppressor proteins p53 and PML. The amyloid precursor protein (APP) is a type I transmembrane protein with unknown physiological function but potential impact in neurodegeneration.