Complete genome sequence of the rifamycin SV-producing Amycolatopsis mediterranei U32 revealed its genetic characteristics in phylogeny and metabolism

Amycolatopsis mediterranei is used for industry-scale production of rifamycin, which plays a vital role in antimyco- bacterial therapy. As the first sequenced genome of the genus Amycolatopsis, the chromosome of strain U32 comprising 10 236 715 base pairs, is one of the largest prokaryotic genomes ever sequenced so far. Unlike the linear topology found in streptomycetes, this chromosome is circular, particularly similar to that of Saccharopolyspora erythraea and Nocardia farcinica, representing their close relationship in phylogeny and taxonomy. Although the predicted 9 228 protein-coding genes in the A. mediterranei genome shared the greatest number of orthologs with those of S. erythraea, it was unexpectedly followed by Streptomyces coelicolor rather than N. farcinica, indicating the distinct metabolic characteristics evolved via adaptation to diverse ecological niches. Besides a core region analogous to that common in streptomycetes, a novel ＇quasicore＇ with typical core characteristics is defined within the non-core region, where 21 out of the total 26 gene clusters for secondary metabolite production are located. The rifamycin biosynthesis gene cluster located in the core encodes a cytochrome P450 enzyme essential for the conversion of rifamycin SV to B, revealed by comparing to the highly homologous cluster of the rifamycin B-producing strain S699 and further confirmed by genetic complementation. The genomic information of A. mediterranei demonstrates a metabolic network orchestrated not only for extensive utilization of various carbon sources and inorganic nitrogen compounds but also for effective funneling of metabolic intermediates into the secondary antibiotic synthesis process under the control of a seemingly complex regulatory mechanism.

Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

Chaperone-mediated autophagy(CMA)is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases.However,the mechanisms that regulate CMA are not fully understood.Here,using unbiased drug screening approaches,we discover Metformin,a drug that is commonly the first medication prescribed for type 2 diabetes,can induce CMA.We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA,Hsc70,and its activation.Notably,we find that amyloid-beta precursor protein(APP)is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner.The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity.Importantly,we find that in the APP/PS1 mouse model of Alzheimer's disease(AD),activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβplaque levels and reverses the molecular and behavioral AD phenotypes.Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases,such as AD,where such therapeutic intervention could be beneficial.

A systematic study of the whole genome sequence of Amycolatopsis methanolica strain 239T provides an insight into its physiological and taxonomic properties which correlate with its position in the genus

The complete genome of methanol-utilizing Amycolatopsis methanolica strain 239T was generated,revealing a single 7,237,391 nucleotide circular chromosome with 7074 annotated protein-coding sequences(CDSs).Comparative analyses against the complete genome sequences of Amycolatopsis japonica strain MG417-CF17T,Amycolatopsis mediterranei strain U32 and Amycolatopsis orientalis strain HCCB10007 revealed a broad spectrum of genomic structures,including various genome sizes,core/quasi-core/non-core configurations and different kinds of episomes.Although polyketide synthase gene clusters were absent from the A.methanolica genome,12 gene clusters related to the biosynthesis of other specialized(secondary)metabolites were identified.Complete pathways attributable to the facultative methylotrophic physiology of A.methanolica strain 239T,including both the mdo/mscR encoded methanol oxidation and the hps/hpi encoded formaldehyde assimilation via the ribulose monophosphate cycle,were identified together with evidence that the latter might be the result of horizontal gene transfer.Phylogenetic analyses based on 16S rDNA or orthologues of AMETH_3452,a novel actinobacterial class-specific conserved gene against 62 or 18 Amycolatopsis type strains,respectively,revealed three major phyletic lineages,namely the mesophilic or moderately thermophilic A.orientalis subclade(AOS),the mesophilic Amycolatopsis taiwanensis subclade(ATS)and the thermophilic A.methanolica subclade(AMS).The distinct growth temperatures of members of the subclades correlated with corresponding genetic variations in their encoded compatible solutes.This study shows the value of integrating conventional taxonomic with whole genome sequence data.

Correction to:Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

CORRECTION TO:PROTEIN CELL HTTPS://DOI.ORG/10.1007/S13238-021-00858-3 In legend of figure 1,this sentence“(C)293THK cells were treated as in a”should be corrected as“(C)293THK cells were treated as in(A)”.In legend of figure 2,“E-64D(10μmol/L)”in description of panel(B)should be removed.In section“Metformin activates chaperone-mediated autophagy”of RESULTS,E-64D in sentence“Metformininduced degradation of HK2 and PKM2 was blocked by lysosomal inhibitors(E-64D,Bafilomycin A1 and Leupeptin+NH4Cl)”should be removed.