Volume 15 Issue 10, October 2013

mTOR is a central controller that integrates many inputs to regulate cell growth and ensure cellular homeostasis. The mTORC1 inhibitor TSC (tuberous sclerosis complex) on the peroxisome is found to inhibit mTORC1 in response to endogenous reactive oxygen species. Thus, mTOR may avoid confounding different inputs by sensing them at different cellular locations.

Cytoplasmic compartments containing misfolded proteins targeted for degradation, named Q-bodies, have been identified. Q-body formation is a dynamic process that actively manages the metastable state of the protein fold through small heat shock proteins and the Hsp70–Hsp90–Hsp110 proteostasis system to promote cellular fitness under both physiological and stress conditions.

The role of RNA splicing in the regulation of stem cell properties has remained largely unexplored. The splicing-associated protein SON is now shown to be necessary for embryonic stem cell maintenance, by influencing the splicing of pluripotency regulators.

Ng and colleagues show that the spliceosome-associated factor SON is essential for the maintenance of pluripotency and the survival of human embryonic stem cells. Using genome-wide RNA profiling to identify SON-regulated transcripts, they find that it modulates splicing of transcripts of pluripotency regulators such as OCT4, PRDM14, E4F1 and MED24.

Skin stem cells are amplified in early development. Yi and colleagues found that miR-205 promotes neonatal skin stem cell expansion by directly targeting negative regulators of PI(3)K–Akt signalling to maintain proliferation.

Adult differentiated cells can be reprogrammed to lineage-restricted proliferating neural precursors in vitro. Zhang and colleagues show that the transcription factor SOX2 is sufficient to reprogram resident astrocytes in the mouse brain to neuroblasts that can proliferate and differentiate following treatment with histone deacetylase inhibitors and differentiating factors BDNF and noggin.

In the Hippo pathway, the atypical cadherins Fat and Dachsous modulate tissue growth. Harvey and colleagues have identified two regulators of the Hippo pathway, the WD40 protein Riquiqui and the DYRK kinase Minibrain, that act downstream of Dachsous to inhibit Wts and promote Yki-dependent tissue growth.

Reactive oxygen species inhibit mTORC1 signalling, but the subcellular localization of this event has been unclear. Walker and colleagues show that the tuberous sclerosis complex (TSC) is located at the peroxisome, where it functions as a Rheb GTPase-activator protein to suppress mTORC1 and induce autophagy. They also show that disease-associated mutations in TCS2 display impaired peroxisome localization and mTORC1 repression.

How injured mitochondria are targeted for autophagic degradation is not well understood. Chu and colleagues find that pro-mitophagy stimuli induce externalization of cardiolipin to the outer mitochondrial membrane of neuronal cells, and find that this is required for binding of the autophagy protein LC3 to mitochondria and mitophagy.

ER–Golgi transport and autophagy are tightly connected. Liang and colleagues find that UVRAG binds to PtdIns(3)P to localize it to the ER, from where, under normal conditions, it regulates the transport of COPI cargo transfer to the ER and Golgi integrity, but from where, following autophagy induction, it dissociates to modulate ATG9 transfer to autophagosomes.

The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection by engaging two distinct exocyst complex proteins: EXO84 to modulate autophagy and SEC5 to regulate innate immune signalling. Sablina and colleagues find that whereas ubiquitylation of RALB at K47 promotes its interaction with SEC5, the de-ubiquitylase USP33 switches RALB to the EXO84–beclin complex to promote autophagy during nutrient starvation.

Quality control of misfolded proteins is thought to involve proteasome-dependent degradation or, if this fails, sequestration into inclusion bodies. Frydman and colleagues reveal the existence of endoplasmic-reticulum-associated structures, termed Q-bodies, that concentrate misfolded proteins in a chaperone-dependent manner before degradation.

Blau and colleagues show that non-dividing heterokaryons between mouse embryonic stem cells and human fibroblasts, in which human nuclei reprogram to a more embryonic state, can be used to identify signalling pathways involved in reprogramming. They delineate that IL-6 signalling and JAK/STAT target kinase Pim1 signalling are induced during this reprogramming, and that they increase the efficiency of factor-mediated reprogramming to induced pluripotent stem cell status.

Actin is abundant in the nuclei of oocytes but its role has been unclear. Feric and Brangwynne find that actin forms a network that prevents the sedimentation of RNA and protein bodies caused by gravitational forces.