The cytosolic domain of Pex22p stimulates the Pex4p-dependent ubiquitination of the PTS1-receptor

Peroxisomal biogenesis is an ubiquitin-dependent process because the receptors required for the import of peroxisomal matrix proteins are controlled via their ubiquitination status. A key step is the monoubiquitination of the import receptor Pex5p by the ubiquitin-conjugating enzyme (E2) Pex4p. This monoubiquitination is supposed to take place after Pex5p has released the cargo into the peroxisomal matrix and primes Pex5p for the extraction from the membrane by the mechano-enzymes Pex1p/Pex6p. These two AAA-type ATPases export Pex5p back to the cytosol for further rounds of matrix protein import. Recently, it has been reported that the soluble Pex4p requires the interaction to its peroxisomal membrane-anchor Pex22p to display full activity. Here we demonstrate that the soluble C-terminal domain of Pex22p harbours its biological activity and that this activity is independent from its function as membrane-anchor of Pex4p. We show that Pex4p can be functionally fused to the trans-membrane segment of the membrane protein Pex3p, which is not directly involved in Pex5p-ubiquitination and matrix protein import. However, this Pex3(N)-Pex4p chimera can only complement the double-deletion strain pex4Δ/pex22Δ and ensure optimal Pex5p-ubiquitination when the C-terminal part of Pex22p is additionally expressed in the cell. Thus, while the membrane-bound portion Pex22(N)p is not required when Pex4p is fused to Pex3(N)p, the soluble Pex22(C)p is essential for peroxisomal biogenesis and efficient monoubiquitination of the import receptor Pex5p by the E3-ligase Pex12p in vivo and in vitro. The results merge into a picture of an ubiquitin-conjugating complex at the peroxisomal membrane consisting of three domains: the ubiquitin-conjugating domain (Pex4p), a membrane-anchor domain (Pex22(N)p) and an enhancing domain (Pex22(C)p), with the membrane-anchor domain being mutually exchangeable, while the Ubc- and enhancer-domains are essential

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Funktionelle Analyse des APP/FE65/TIP60-Komplexes unter Verwendung eines shRNA-vermittelten Knockdowns in humaner Zellkultur

In dieser Arbeit wurden zwei humane Zellkulturmodelle mit reprimierten Komponenten des Alzheimer-relevanten AFT-Komplexes generiert (Knockdown der APP-Proteinfamilie & Knockdown des FE65-Adapterproteins). Anschließend wurden unbekannte Kandidatenproteine mittels differenzieller Analytik massenspektrometrisch identifiziert und potenzielle Signalwege charakterisiert, sowie validierte Kandidatenproteine funktionell untersucht. Die Knockdown-Studie der APP-Proteinfamilie zeigte, dass die APP-Proteinfamilie eine Rolle im zellulären Methylierungsmechanismus einnimmt, wobei dieser Prozess durch das Enzym MAT2A vermittelt wird. In der FE65-Knockdown-Studie wurden differenziell regulierte Proteine identifiziert und validiert, welche eine entscheidende Rolle bei der DNA-Reparatur und bei DNA Replikationsprozessen einnehmen (z.B. MCM3 und BLM). Des Weiteren wurde entdeckt, dass der FE65/TIP60-Komplex dynamische nukleäre Sphären bildet, welche die Fähigkeit aufweisen, miteinander zu fusionieren

Key players in neurodegenerative disorders in focus-new insights into the proteomic profile of alzheimer's disease, schizophrenia, ALS, and multiple sclerosis: 24th HUPO BPP workshop

The HUPO Brain Proteome Project (HUPO BPP) held its 24th workshop in Vancouver, Canada, September 29, 2015. The focus of the autumn workshop was on new insights into the proteomic profile of Alzheimer's disease, schizophrenia, ALS and multiple sclerosis16710471050Lea T. Grinberg is supported by LIM-22 University of São Paulo Medical School,National Institute of Health (R01AG040311), John Douglas French Alzheimer Foundation and Albert Einstein Research Institute – São Paulo. Young Mok Parkis supported by a grant (2009K001266) from Brain Research Center, The 21st Century Frontier Research Program of the Ministry of Education, Science and Technology, Republic of Kore

Early Diagnosis of Neurodegenerative Diseases - The Long Awaited Holy Grail and Bottleneck of Modern Brain Research - 19th HUPO BPP Workshop

The HUPO Brain Proteome Project (HUPO BPP) held its 19th workshop in Dortmund, Germany, from May 22 to 24, 2013. The focus of the spring workshop was on strategies and developments concerning early diagnosis of neurodegenerative diseases

Early Diagnosis of Neurodegenerative Diseases – The Long Awaited Holy Grail and Bottleneck of Modern Brain Research – 19th HUPO BPP Workshop

The HUPO Brain Proteome Project (HUPO BPP) held its 19th workshop in Dortmund, Germany, from May 22 to 24, 2013. The focus of the spring workshop was on strategies and developments concerning early diagnosis of neurodegenerative diseases

Challenges in Modern Biomarker Discovery – 17th HUPO BPP Workshop

The HUPO Brain Proteome Project (HUPO BPP) held its 17(th) workshop in Sao Paulo, Brazil, on May 24 and 25, 2012. The focus was on the progress on the Human Brain Proteome Atlas as well as ideas, strategies and methodological aspects in clinical neuroproteomics

Developing New Methods to Answer Old and New Questions in Neurodegenerative Diseases

The HUPO Brain Proteome Project (HUPO BPP) held its 21(st) workshop in Honolulu, Hawaii. During the 23-24 January 2014 the island became the center of the open workshop of the scientific community