Just time for a quick run down of highlights from today's new issue of the JCB...
Let's start with our cover image, from Mari et al., which shows the de novo formation of a double-membraned vesicle around cargo destined for the lysosome - an early stage of the degradative autophagy and biosynthetic Cvt pathways. A vital question in the autophagy field is where these early membranes come from. Mari et al. try to answer this question in yeast by following the movements of a protein called Atg9 - an early-acting part of the autophagy machinery and the only conserved transmembrane component. The researchers found that Atg9 localizes to clusters of vesicles and tubules in the vicinity of mitochondria. These clusters, or "Atg9 reservoirs" seem to represent a novel organelle that arises from the ER and/or the Golgi. When autophagy begins, the clusters move en masse to a site near the yeast vacuole/lysosome called the phagophore assembly site where construction of the double-membraned autophagosome is initiated. Senior author Fulvio Reggiori tells me here that the reservoirs may provide a rapid source of membranes for cells to initiate autophagy in times of stress.
Meanwhile, Winslow et al. reveal that the early steps of autophagosome formation are disrupted by alpha-synuclein – a protein that is often mutated or overexpressed in familial forms of Parkinson’s disease. alpha-synuclein blocked autophagosome formation by inhibiting the small GTPase Rab1a, which has a well-established function in controlling membrane transport from the ER to the Golgi. Overexpressing alpha-synuclein or knocking down Rab1 mislocalized Atg9 in mammalian cells and prevented the formation of putative autophagosome precursors called omegasomes. Lead author David Rubinsztein explains here that compromising autophagy in this way could enhance the gradual accumulation of toxic proteins and dysfunctional mitochondria, sensitizing neurons to cell death.
Elsewhere, Chairoungdua et al. uncover a novel way for cells to downregulate the Wnt signaling protein beta-catenin. In the absence of a Wnt signal, beta-catenin is targeted for degradation by the proteasome, but Chairoungdua and colleagues reveal that the protein can also be ejected from the cell in small vesicles known as exosomes. beta-catenin’s incorporation into exosomes is boosted by two members of the tetraspanin family of transmembrane proteins. Both of these tetraspanins are suppressors of tumor metastasis whose expression is lost in several types of late stage tumors, suggesting that the process may be an important way of keeping Wnt signaling under control. You can read more about this surprising mechanism in this week's In Focus.
We also have 2 papers on bone morphogenesis in today's issue. The first, from Bozec et al. reports that the transcription factor Fra-2 regulates bone formation by controlling osteoblast differentiation and collagen production. Meanwhile, Nistala et al. reveal that fibrillin 1 and 2 - both components of the extracellular matrix - regulate bone formation by controlling the availability of TGFbeta and BMP. You can read more about this latter finding in the accompanying commentary by Rifkin and Todorovic and hear directly from the lead author - Francesco Ramirez - in this month's biobytes podcast, also out today. You'll also hear me interview Andrew Belmont about his lab's recent description of the different ways chromatin domains fold up in different cell types. You can listen below or download the podcast from iTunes.
Finally for today, I'll quickly point you in the direction of the latest in our "The Cell Biology of..." series. This time, Ching-Hwa Sung and Jen-Zen Chuang guide us through the Cell Biology of Vision and the fascinating processes occurring in photoreceptors.
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