Autophagy involvement in oncogenesis.

Various clinical and experimental findings have revealed the causal relationship between autophagy failure and oncogenesis, and several mechanisms have been suggested to explain this relationship. We recently proposed two additional mechanisms: centrosome number dysregulation and the failure of autophagic cell death. Here, we detail the mechanical relationship between autophagy failure and oncogenesis.

Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages.

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn's disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7f/f and LysM-cre; Atg7f/f mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7f/f mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix4 upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.

Association Between Atg5-independent Alternative Autophagy and Neurodegenerative Diseases.

Autophagy is a cellular process that degrades intracellular components, including misfolded proteins and damaged organelles. Many neurodegenerative diseases are considered to progress via the accumulation of misfolded proteins and damaged organelles; therefore, autophagy functions in regulating disease severity. There are at least two types of autophagy (canonical autophagy and alternative autophagy), and canonical autophagy has been applied to therapeutic strategies against various types of neurodegenerative diseases. In contrast, the role of alternative autophagy has not yet been clarified, but it is speculated to be involved in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease.

Prediction of intracellular targets of a small compound by analyzing peptides presented on MHC class I.

In chemical biology, the elucidation of chemical target is crucial for successful drug development. Because MHC class I molecules present peptides from intracellular damaged proteins, it might be possible to identify targets of a chemical by analyzing peptide sequences on MHC class I. Therefore, we treated cells with the autophagy-inducing chemical TMD-457 and identified the peptides presented on MHC class I. Many of the peptides were derived from molecules involved in ER trafficking and ER stress, which were confirmed by morphological and biochemical analyses. Therefore, our results demonstrate that analyzing MHC class I peptides is useful for the detection of chemical targets.

Autophagy controls centrosome number by degrading Cep63.

Centrosome number is associated with the chromosome segregation and genomic stability. The ubiquitin-proteasome system is considered to be the main regulator of centrosome number. However, here we show that autophagy also regulates the number of centrosomes. Autophagy-deficient cells carry extra centrosomes. The autophagic regulation of centrosome number is dependent on a centrosomal protein of 63 (Cep63) given that cells lacking autophagy contain multiple Cep63 dots that are engulfed and digested by autophagy in wild-type cells, and that the upregulation of Cep63 increases centrosome number. Cep63 is recruited to autophagosomes via interaction with p62, a molecule crucial for selective autophagy. In vivo, hematopoietic cells from autophagy-deficient and p62-/- mice also contained multiple centrosomes. These results indicate that autophagy controls centrosome number by degrading Cep63.

An FGF4-FRS2alpha-Cdx2 axis in trophoblast stem cells induces Bmp4 to regulate proper growth of early mouse embryos.

A variety of stem cells are controlled by the actions of multiple growth factors in vitro. However, it remains largely unclear how growth factors control the proliferation and differentiation of stem cells in vivo. Here, we describe a novel paracrine mechanism for regulating a stem cell niche in early mammalian embryos, which involves communication between the inner cell mass (ICM) and the trophectoderm, from which embryonic stem (ES) cells and trophoblast stem (TS) cells can be derived, respectively. It is known that ES cells produce fibroblast growth factor (FGF)4 and that TS cells produce bone morphogenetic protein (Bmp)4. We provide evidence that FRS2alpha mediates activation of the extracellular signal-regulated progein kinase (ERK) pathway to enhance expression of transcription factor Cdx2 in TS cells in response to FGF4. Cdx2 in turn binds to an FGF4-responsive enhancer element of the promoter region of Bmp4, leading to production and secretion of Bmp4. Moreover, exogenous Bmp4 is able to rescue the defective growth of Frs2alpha-null ICM. These findings suggest an important role of Cdx2 for production of Bmp4 in TS cells to promote the proper growth of early mouse embryos.