Ubiquitin and UBL (ubiquitin-like) modifiers are small proteins that covalently modify other proteins to alter their properties or behaviours. Ubiquitin modification (ubiquitylation) targets many substrates, often leading to their proteasomal degradation. NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is the UBL most closely related to ubiquitin, and its best-studied role is the activation of CRLs (cullin-RING ubiquitin ligases) by its conjugation to a conserved C-terminal lysine residue on cullin proteins. The attachment of UBLs requires three UBL-specific enzymes, termed E1, E2 and E3, which are usually well insulated from parallel UBL pathways. In the present study, we report a new mode of NEDD8 conjugation (NEDDylation) whereby the UBL NEDD8 is linked to proteins by ubiquitin enzymes in vivo. We found that this atypical NEDDylation is independent of classical NEDD8 enzymes, conserved from yeast to mammals, and triggered by an increase in the NEDD8 to ubiquitin ratio. In cells, NEDD8 overexpression leads to this type of NEDDylation by increasing the concentration of NEDD8, whereas proteasome inhibition has the same effect by depleting free ubiquitin. We show that bortezomib, a proteasome inhibitor used in cancer therapy, triggers atypical NEDDylation in tissue culture, which suggests that a similar process may occur in patients receiving this treatment.
Belizean health policy supports a primary health care (PHC) strategy of universal access, community participation, and multisectoral collaboration. The principals of PHC were a key part of Belize's emergent national identity and built on existing community-based health strategies. Ethnographic research in western Belize, however, reveals that ongoing health reform is removing providers from participatory arenas. In this article, we foreground a particular moment in Belizean health history--the rise and demise of multisectoral collaboration--to question what can constitute meaningful community participation in the midst of health reform. Many allied health providers continue to believe in the potential of PHC to alleviate the structural causations of poor health and to invest in PHC despite a lack of state support. This means that providers, the majority women, are palliating the consequences of neoliberal reform; it also means that they provide spaces of contestation to the consumer "logic" of this reform.
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