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1.
Sci Rep ; 13(1): 5333, 2023 04 01.
Article in English | MEDLINE | ID: mdl-37005459

ABSTRACT

The majority of proteins in mammalian cells are modified by covalent attachment of an acetyl-group to the N-terminus (Nt-acetylation). Paradoxically, Nt-acetylation has been suggested to inhibit as well as to promote substrate degradation. Contrasting these findings, proteome-wide stability measurements failed to detect any correlation between Nt-acetylation status and protein stability. Accordingly, by analysis of protein stability datasets, we found that predicted Nt-acetylation positively correlates with protein stability in case of GFP, but this correlation does not hold for the entire proteome. To further resolve this conundrum, we systematically changed the Nt-acetylation and ubiquitination status of model substrates and assessed their stability. For wild-type Bcl-B, which is heavily modified by proteasome-targeting lysine ubiquitination, Nt-acetylation did not correlate with protein stability. For a lysine-less Bcl-B mutant, however, Nt-acetylation correlated with increased protein stability, likely due to prohibition of ubiquitin conjugation to the acetylated N-terminus. In case of GFP, Nt-acetylation correlated with increased protein stability, as predicted, but our data suggest that Nt-acetylation does not affect GFP ubiquitination. Similarly, in case of the naturally lysine-less protein p16, Nt-acetylation correlated with protein stability, regardless of ubiquitination on its N-terminus or on an introduced lysine residue. A direct effect of Nt-acetylation on p16 stability was supported by studies in NatB-deficient cells. Together, our studies argue that Nt-acetylation can stabilize proteins in human cells in a substrate-specific manner, by competition with N-terminal ubiquitination, but also by other mechanisms that are independent of protein ubiquitination status.


Subject(s)
Lysine , Proteome , Animals , Humans , Lysine/metabolism , Proteome/metabolism , Acetylation , Protein Processing, Post-Translational , Ubiquitination , Mammals/metabolism
2.
J Alzheimers Dis ; 87(1): 51-81, 2022.
Article in English | MEDLINE | ID: mdl-35275527

ABSTRACT

Alzheimer's disease (AD) is the most common form of dementia and typically characterized by the accumulation of amyloid-ß plaques and tau tangles. Intriguingly, there also exists a group of elderly which do not develop dementia during their life, despite the AD neuropathology, the so-called non-demented individuals with AD neuropathology (NDAN). In this review, we provide extensive background on AD pathology and normal aging and discuss potential mechanisms that enable these NDAN individuals to remain cognitively intact. Studies presented in this review show that NDAN subjects are generally higher educated and have a larger cognitive reserve. Furthermore, enhanced neural hypertrophy could compensate for hippocampal and cingulate neural atrophy in NDAN individuals. On a cellular level, these individuals show increased levels of neural stem cells and 'von Economo neurons'. Furthermore, in NDAN brains, binding of Aß oligomers to synapses is prevented, resulting in decreased glial activation and reduced neuroinflammation. Overall, the evidence stated here strengthens the idea that some individuals are more resistant to AD pathology, or at least show an elongation of the asymptomatic state of the disease compared to others. Insights into the mechanisms underlying this resistance could provide new insight in understanding normal aging and AD itself. Further research should focus on factors and mechanisms that govern the NDAN cognitive resilience in order to find clues on novel biomarkers, targets, and better treatments of AD.


Subject(s)
Alzheimer Disease , Aged , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Hippocampus/pathology , Humans , Plaque, Amyloid/pathology , Synapses/metabolism
3.
Mol Syst Biol ; 16(7): e8955, 2020 07.
Article in English | MEDLINE | ID: mdl-32696599

ABSTRACT

Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNα signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNα dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNα leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNα signal response.


Subject(s)
Feedback, Physiological/drug effects , Hepatocytes/metabolism , Interferon-alpha/pharmacology , STAT1 Transcription Factor/metabolism , STAT2 Transcription Factor/metabolism , Signal Transduction/drug effects , Cell Line, Tumor , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Hepatocytes/drug effects , Humans , Interferon Regulatory Factor-2/genetics , Interferon Regulatory Factor-2/metabolism , Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics , Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism , Models, Theoretical , RNA, Small Interfering , STAT1 Transcription Factor/genetics , STAT2 Transcription Factor/genetics , Signal Transduction/genetics , Software , Suppressor of Cytokine Signaling 1 Protein/genetics , Suppressor of Cytokine Signaling 1 Protein/metabolism , Suppressor of Cytokine Signaling 3 Protein/genetics , Suppressor of Cytokine Signaling 3 Protein/metabolism , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism
4.
Respir Med ; 102(2): 198-204, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17996435

ABSTRACT

Sexual quality of life was examined in 55 outpatients with chronic obstructive pulmonary disease (COPD) and asthma, using disease-specific questionnaires. Compared to an age- and sex-matched norm group, male patients with COPD reported a significantly lower sexual quality of life on all dimensions of the questionnaire. Female patients with COPD reported a lower frequency of sexual intimacy and lower sexual quality of life overall. Patients with asthma reported sexual quality-of-life scores that were somewhat better than COPD patients but worse than the healthy control group. Patients reported that they did not discuss sexual quality-of-life issues with their physician. Sexuality needs to be discussed by the health care provider in the consultation in order to improve quality of life of patients with chronic respiratory disorders.


Subject(s)
Asthma/psychology , Pulmonary Disease, Chronic Obstructive/psychology , Quality of Life/psychology , Sexual Dysfunction, Physiological/psychology , Female , Humans , Male , Middle Aged , Physician-Patient Relations/ethics , Sickness Impact Profile , Surveys and Questionnaires
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