Ube2W conjugates ubiquitin to α-amino groups of protein N-termini.

The covalent attachment of the protein ubiquitin to intracellular proteins by a process known as ubiquitylation regulates almost all major cellular systems, predominantly by regulating protein turnover. Ubiquitylation requires the co-ordinated action of three enzymes termed E1, E2 and E3, and typically results in the formation of an isopeptide bond between the C-terminal carboxy group of ubiquitin and the ϵ-amino group of a target lysine residue. However, ubiquitin is also known to conjugate to the thiol of cysteine residue side chains and the α-amino group of protein N-termini, although the enzymes responsible for discrimination between different chemical groups have not been defined. In the present study, we show that Ube2W (Ubc16) is an E2 ubiquitin-conjugating enzyme with specific protein N-terminal mono-ubiquitylation activity. Ube2W conjugates ubiquitin not only to its own N-terminus, but also to that of the small ubiquitin-like modifier SUMO (small ubiquitin-related modifier) in a manner dependent on the SUMO-targeted ubiquitin ligase RNF4 (RING finger protein 4). Furthermore, N-terminal mono-ubiquitylation of SUMO-2 primes it for poly-ubiquitylation by the Ubc13-UEV1 (ubiquitin-conjugating enzyme E2 variant 1) heterodimer, showing that N-terminal ubiquitylation regulates protein fate. The description in the present study is the first of an E2-conjugating enzyme with N-terminal ubiquitylation activity, and highlights the importance of E2 enzymes in the ultimate outcome of E3-mediated ubiquitylation.

Chronic cough in Germany: results from a general-population survey.

BACKGROUND: Chronic cough (CC) which is defined ≥8 weeks is a common condition in clinical practice. However, estimates of prevalence and associated comorbidities in German adults and key subgroups of age and gender are lacking. METHODS: Cross-sectional study based on a representative panel of 15 020 adult subjects of the general population who completed the German National Health and Wellness Survey, reporting CC and questions about comorbidities. Lifetime and 12-month prevalence are presented as unweighted estimates. RESULTS: The lifetime CC prevalence was 6.5% (range across age groups 5.1%-8.3%) and the 12-month prevalence was 4.9% (range 3.7-5.7%). The prevalence of diagnosed CC was 2.8% (range 0.9-4.1%) and the prevalence of persons currently on any prescription to treat CC was 0.6% (range 0.2-1.4%). Respondents who experienced CC were 52.0±17.0 years old, with a higher prevalence in those aged 50 years and older. Persons with CC had higher morbidity scores and were diagnosed with an increased number of comorbidities, most frequently diagnoses of the respiratory system (71.0%), followed by digestive tract disorders (34.0%) and sleep disorders (37.6%). CONCLUSIONS: In a broadly representative sample of German adults, lifetime and 12-month prevalence of CC was greatest in current and former smokers and those older ≥50 years of age. Comorbidities are frequent and may complicate management of these patients.