Membrane supply and remodeling during autophagosome biogenesis

The de novo generation of double-membrane autophagosomes is the hallmark of autophagy. The initial membranous precursor cisterna, the phagophore, is very likely generated by the fusion of vesicles and acts as a membrane seed for the subsequent expansion into an autophagosome. This latter step requires a massive convoy of lipids into the phagophore. In this review, we present recent advances in our understanding of the intracellular membrane sources and lipid delivery mechanisms, which principally rely on vesicular transport and membrane contact sites that contribute to autophagosome biogenesis. In this context, we discuss lipid biosynthesis and lipid remodeling events that play a crucial role in both phagophore nucleation and expansion

Evaluating diagnosis and treatment of oral and esophageal candidiasis in Ugandan AIDS patients.

A randomized cross-over clinical and endoscopic evaluation of 85 Ugandan patients showed that esophageal candidiasis in AIDS patients with oral candidiasis could be managed without endoscopy and biopsies. Oral lesions, especially when accompanied by esophageal symptoms, were sufficient for diagnosis. Miconazole was more effective than nystatin in treating esophageal candidiasis and could be a valid alternative to more expensive azolic drugs in developing countries

The puzzling origin of the autophagosomal membrane

Autophagy is one of the newest and fastest emerging research areas in biomedical life sciences. Autophagosomes, large double-membrane vesicles enclosing cytoplasmic components targeted for degradation, are the hallmark of this catabolic pathway. The origin of the lipid bilayers composing these transport carriers has been the central enigma of the field since the discovery of autophagy. A series of recent studies has implicated several cellular organelles as the possible source of the autophagosomal membranes, if anything further clouding our view. In this compendium, we will discuss these apparently contradictory results and briefly emphasize the relevance of determining the lipid source used for autophagy for future translational research, for example in drug discovery programs

WDR45, one gene associated with multiple neurodevelopmental disorders

The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ss-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat beta-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders

Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane

BACKGROUND: Misfolded proteins are generally recognised by cellular quality control machinery, which typically results in their ubiquitination and degradation. For soluble cytoplasmic proteins, degradation is mediated by the proteasome. Membrane proteins that fail to fold correctly are subject to ER associated degradation (ERAD), which involves their extraction from the membrane and subsequent proteasome-dependent destruction. Proteins with abnormal transmembrane domains can also be recognised in the Golgi or endosomal system and targeted for destruction in the vacuole/lysosome. It is much less clear what happens to membrane proteins that reach their destination, such as the cell surface, and then suffer damage. METHODOLOGY/PRINCIPAL FINDINGS: We have tested the ability of yeast cells to degrade membrane proteins to which temperature-sensitive cytoplasmic alleles of the Ura3 protein or of phage lambda repressor have been fused. In soluble form, these proteins are rapidly degraded upon temperature shift, in part due to the action of the Doa10 and San1 ubiquitin ligases and the proteasome. When tethered to the ER protein Use1, they are also degraded. However, when tethered to a plasma membrane protein such as Sso1 they escape degradation, either in the vacuole or by the proteasome. CONCLUSIONS/SIGNIFICANCE: Membrane proteins with a misfolded cytoplasmic domain appear not to be efficiently recognised and degraded once they have escaped the ER, even though their defective domains are exposed to the cytoplasm and potentially to cytoplasmic quality controls. Membrane tethering may provide a way to reduce degradation of unstable proteins