Nature Cell Biology 10, 556 (2008). doi:10.1038/ncb1718

Authors: Jason M. Kinchen, Kimon Doukoumetzidis, Johann Almendinger, Lilli Stergiou, Annie Tosello-Trampont, Costi D. Sifri, Michael O. Hengartner & Kodi S. Ravichandran

Removal of apoptotic cells is critical for the physiological well-being of the organism and defects in corpse removal have been linked to disease states. Genes regulating corpse recognition and internalization have been identified, but few molecules involved in the processing of internalized corpses are known. Through a combination of targeted and unbiased reverse genetic screens in Caenorhabditis elegans, and studies in mammalian cells, we have identified genes required for maturation of apoptotic-cell-containing phagosomes. We have further ordered these candidates, which include the GTPases RAB-5 and RAB-7 and the HOPS complex, into a coherent linear pathway for the maturation of apoptotic cells within phagosomes. In depth analysis of two additional candidate genes, the phosphatidylinositol 3 kinase (PI(3)K) vps-34 (A001762) and dyn-1/dynamin, showed an accumulation of internalized, but undegraded, corpses within abnormal Rab5-negative phagosomes. We ordered these candidates in our pathway, with DYN-1 functioning upstream of VPS-34 in the recruitment and/or retention of RAB-5 to the phagosome. Finally, we have also identified a previously undescribed biochemical complex containing Vps34, dynamin and Rab5GDP, thus providing a mechanism for Rab5 recruitment to the nascent phagosome.

Nature Cell Biology 10, 567 (2008). doi:10.1038/ncb1719

Authors: Koshiro Monzen, Yuzuru Ito, Atsuhiko T. Naito, Hiroki Kasai, Yukio Hiroi, Doubun Hayashi, Ichiro Shiojima, Tsutomu Yamazaki, Kohei Miyazono, Makoto Asashima, Ryozo Nagai & Issei Komuro

The high mobility group (HMG) of nuclear proteins regulates expression of many genes through architectural remodelling of the chromatin structure, and formation of multiprotein complexes on promoter/enhancer regions. This leads to the active transcription of their target genes. Here we show that HMGA2, a member of the HMGA sub-family of HMG proteins, has a critical function in cardiogenesis. Overexpression of HMGA2 enhanced, whereas siRNA-mediated knockdown of HMGA2 blocked, cardiomyocyte differentiation of the embryonal carcinoma cell line P19CL6. Moreover, overexpression of a dominant-negative HMGA2 or morpholino-mediated knockdown of HMGA2 expression blocked normal heart formation in Xenopus laevis embryos, suggesting that HMGA2 has an important role in cardiogenesis both in vitro and in vivo. Mechanistically, HMGA2 associated with Smad1/4 and showed synergistic trans-activation of the gene for a cardiac transcription factor Nkx2.5; a conserved HMGA2 binding site was required for the promoter activity of Nkx2.5 gene, both in P19CL6 cells and in transgenic Xenopus embryos. Thus, HMGA2 is a positive regulator of Nkx2.5 gene expression and is essential for normal cardiac development.

Nature Cell Biology 10, 575 (2008). doi:10.1038/ncb1720

Authors: Clas B. Johansson, Sawsan Youssef, Kassie Koleckar, Colin Holbrook, Regis Doyonnas, Stephane Y. Corbel, Lawrence Steinman, Fabio M. V. Rossi & Helen M. Blau

Transplanted bone marrow-derived cells (BMDCs) have been reported to fuse with cells of diverse tissues, but the extremely low frequency of fusion has led to the view that such events are biologically insignificant. Nonetheless, in mice with a lethal recessive liver disease (tyrosinaemia), transplantation of wild-type BMDCs restored liver function by cell fusion and prevented death, indicating that cell fusion can have beneficial effects. Here we report that chronic inflammation resulting from severe dermatitis or autoimmune encephalitis leads to robust fusion of BMDCs with Purkinje neurons and formation of hundreds of binucleate heterokaryons per cerebellum, a 10–100-fold higher frequency than previously reported. Single haematopoietic stem-cell transplants showed that the fusogenic cell is from the haematopoietic lineage and parabiosis experiments revealed that fusion can occur without irradiation. Transplantation of rat bone marrow into mice led to activation of dormant rat Purkinje neuron-specific genes in BMDC nuclei after fusion with mouse Purkinje neurons, consistent with nuclear reprogramming. The precise neurological role of these heterokaryons awaits elucidation, but their frequency in brain after inflammation is clearly much higher than previously appreciated.

Nature Cell Biology 10, 584 (2008). doi:10.1038/ncb1721

Authors: Jens M. Nygren, Karina Liuba, Martin Breitbach, Simon Stott, Lina Thorén, Wilhelm Roell, Caroline Geisen, Philipp Sasse, Deniz Kirik, Anders Björklund, Claus Nerlov, Bernd K. Fleischmann, Stefan Jovinge & Sten Eirik W. Jacobsen

Recent studies have suggested that regeneration of non-haematopoietic cell lineages can occur through heterotypic cell fusion with haematopoietic cells of the myeloid lineage. Here we show that lymphocytes also form heterotypic-fusion hybrids with cardiomyocytes, skeletal muscle, hepatocytes and Purkinje neurons. However, through lineage fate-mapping we demonstrate that such in vivo fusion of lymphoid and myeloid blood cells does not occur to an appreciable extent in steady-state adult tissues or during normal development. Rather, fusion of blood cells with different non-haematopoietic cell types is induced by organ-specific injuries or whole-body irradiation, which has been used in previous studies to condition recipients of bone marrow transplants. Our findings demonstrate that blood cells of the lymphoid and myeloid lineages contribute to various non-haematopoietic tissues by forming rare fusion hybrids, but almost exclusively in response to injuries or inflammation.

Nature Cell Biology 10, 593 (2008). doi:10.1038/ncb1722

Authors: Philip A. Gregory, Andrew G. Bert, Emily L. Paterson, Simon C. Barry, Anna Tsykin, Gelareh Farshid, Mathew A. Vadas, Yeesim Khew-Goodall & Gregory J. Goodall

Epithelial to mesenchymal transition (EMT) facilitates tissue remodelling during embryonic development and is viewed as an essential early step in tumour metastasis. We found that all five members of the microRNA-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) and miR-205 were markedly downregulated in cells that had undergone EMT in response to transforming growth factor (TGF)-β or to ectopic expression of the protein tyrosine phosphatase Pez. Enforced expression of the miR-200 family alone was sufficient to prevent TGF-β-induced EMT. Together, these microRNAs cooperatively regulate expression of the E-cadherin transcriptional repressors ZEB1 (also known as δEF1) and SIP1 (also known as ZEB2), factors previously implicated in EMT and tumour metastasis. Inhibition of the microRNAs was sufficient to induce EMT in a process requiring upregulation of ZEB1 and/or SIP1. Conversely, ectopic expression of these microRNAs in mesenchymal cells initiated mesenchymal to epithelial transition (MET). Consistent with their role in regulating EMT, expression of these microRNAs was found to be lost in invasive breast cancer cell lines with mesenchymal phenotype. Expression of the miR-200 family was also lost in regions of metaplastic breast cancer specimens lacking E-cadherin. These data suggest that downregulation of the microRNAs may be an important step in tumour progression.

Nature Cell Biology 10, 602 (2008). doi:10.1038/ncb1723

Authors: Claudine Kraft, Anna Deplazes, Marc Sohrmann & Matthias Peter

Eukaryotic cells use autophagy and the ubiquitin–proteasome system (UPS) as their major protein degradation pathways. Whereas the UPS is required for the rapid degradation of proteins when fast adaptation is needed, autophagy pathways selectively remove protein aggregates and damaged or excess organelles. However, little is known about the targets and mechanisms that provide specificity to this process. Here we show that mature ribosomes are rapidly degraded by autophagy upon nutrient starvation in Saccharomyces cerevisiae. Surprisingly, this degradation not only occurs by a non-selective mechanism, but also involves a novel type of selective autophagy, which we term 'ribophagy'. A genetic screen revealed that selective degradation of ribosomes requires catalytic activity of the Ubp3p/Bre5p ubiquitin protease. Although ubp3Δ and bre5Δ cells strongly accumulate 60S ribosomal particles upon starvation, they are proficient in starvation sensing and in general trafficking and autophagy pathways. Moreover, ubiquitination of several ribosomal subunits and/or ribosome-associated proteins was specifically enriched in ubp3Δ cells, suggesting that the regulation of ribophagy by ubiquitination may be direct. Interestingly, ubp3Δ cells are sensitive to rapamycin and nutrient starvation, implying that selective degradation of ribosomes is functionally important in vivo. Taken together, our results suggest a link between ubiquitination and the regulated degradation of mature ribosomes by autophagy.

Nature Cell Biology 10, 611 (2008). doi:10.1038/ncb1724

Authors: Keiko Kawauchi, Keigo Araki, Kei Tobiume & Nobuyuki Tanaka

Cancer cells use aerobic glycolysis preferentially for energy provision and this metabolic change is important for tumour growth. Here, we have found a link between the tumour suppressor p53, the transcription factor NF-κB and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKKα and IKKβ and subsequent NF-κB activity were enhanced. Activation of NF-κB, by loss of p53, caused an increase in the rate of aerobic glycolysis and upregulation of Glut3. Oncogenic Ras-induced cell transformation and acceleration of aerobic glycolysis in p53-deficient cells were suppressed in the absence of p65/NF-κB expression, and were restored by GLUT3 expression. It was also shown that a glycolytic inhibitor diminished the enhanced IKK activity in p53-deficient cells. Moreover, in Ras-expressing p53-deficient cells, IKK activity was suppressed by p65 deficiency and restored by GLUT3 expression. Taken together, these data indicate that p53 restricts activation of the IKK–NF-κB pathway through suppression of glycolysis. These results suggest that a positive-feedback loop exists, whereby glycolysis drives IKK–NF-κB activation, and that hyperactivation of this loop by loss of p53 is important in oncogene-induced cell transformation.

Nature Cell Biology 10, 625 (2008). doi:10.1038/ncb1726

Authors: Susana Ubeda-Tomás, Ranjan Swarup, Juliet Coates, Kamal Swarup, Laurent Laplaze, Gerrit T.S. Beemster, Peter Hedden, Rishikesh Bhalerao & Malcolm J. Bennett

Gibberellins (GAs) are key regulators of plant growth and development. They promote growth by targeting the degradation of DELLA repressor proteins; however, their site of action at the cellular, tissue or organ levels remains unknown. To map the site of GA action in regulating root growth, we expressed gai, a non-degradable, mutant DELLA protein, in selected root tissues. Root growth was retarded specifically when gai was expressed in endodermal cells. Our results demonstrate that the endodermis represents the primary GA-responsive tissue regulating organ growth and that endodermal cell expansion is rate-limiting for elongation of other tissues and therefore of the root as a whole.

Nature Cell Biology 10, 499 (2008). doi:10.1038/ncb0508-499

Is scientific progress being stifled by a lack of support for researchers who aim to change research directions?

Nature Cell Biology 10, 501 (2008). doi:10.1038/ncb0508-501

Author: Eric A. Miska

During epithelial–mesenchymal transition (EMT) cells loosen their intercellular contacts and leave the epithelial layer. Three microRNA (miRNA) families modulate EMT upstream of the key cell-adhesion protein E-cadherin, highlighting the potential importance of miRNAs in EMT-dependent processes, such as mesoderm development and tumour metastasis.

Nature Cell Biology 10, 503 (2008). doi:10.1038/ncb0508-503

Authors: Ilyas Singec & Evan Y. Snyder

Sporadic fusion of bone-marrow-derived cells with those of developmentally unrelated structures following transplantation has previously been regarded solely as an artefact, leading to the misinterpretation that cells could 'transdifferentiate'. We now learn that heterotypic cell fusion of myelo-lymphoid cells with non-haematopoietic cells is enhanced during chronic inflammation, raising new questions about the biological significance of this controversial phenomenon.

Nature Cell Biology 10, 505 (2008). doi:10.1038/ncb0508-505

Authors: Hitoshi Nakatogawa & Yoshinori Ohsumi

Autophagy is a process in which cytoplasmic components are broken down to supply materials for the synthesis of essential molecules under nutrient-limiting conditions. Because this process involves random sequestration of the cytoplasm by large membrane vesicles, considerable amounts of molecules, such as ribosomes, are necessarily degraded by autophagy. However, starving cells also promote additional selective degradation of ribosomes as a requirement for survival.

Nature Cell Biology 10, 507 (2008). doi:10.1038/ncb0508-507

Authors: Kevin Petrie & Arthur Zelent

SUMOylation of PML–RARα oncoprotein has been linked to its arsenic-induced degradation and the therapeutic response in acute promyelocytic leukaemia. Two groups identify PML as an in vivo target of the RING finger ubiquitin E3 ligase RNF4, which specifically binds polySUMOylated PML and is essential for the arsenic-induced catabolism of both PML and PML–RARα.

Nature Cell Biology 10, 509 (2008). doi:10.1038/ncb0508-509

Author: Laura Serna

Plant stomata, which consist of paired guard cells placed on the surface of leaves, control gas exchange with the atmosphere. Anion transport by unidentified guard-cell channels closes the stomatal pore and the first component for this channel function has now been found.