Previous work has identified roles for the protein kinase PINK1 and the ubiquitin ligase PARKIN in the synthesis of ubiquitin chains on the surface of mitochondria in response to mitochondrial damage. But how these ubiquitin chains target damaged mitochondria to autophagosomes for “mitophagy” and the regulation of this process remained unclear. New work from the Harper Lab, published in Molecular Cell, defines a mechanism in which ubiquitin chains on mitochondria recruit 4 autophagy adaptors (OPTN, NDP52, p62, and TAX1BP1) through their ubiquitin binding domains to specific foci on damaged mitochondria. This recruitment leads to activation of the TBK1 kinase, which associates with OPTN, NDP52, and p62. In a concerted fashion, TBK1 phosphorylates OPTN, NDP52, and p62. Biochemical studies demonstrated that phosphorylation of OPTN by TBK1 further stimulates its intrinsic ubiquitin binding activity. Thus, this mechanism provides a self-reinforcing system that links these ubiquitin binding autophagy receptors with damaged mitochondria. Importantly, recent work has demonstrated that both TBK1 and OPTN are mutated in ALS. Thus, this work demonstrates that genes mutated in Parkinson’s Disease and ALS function in a common signal transduction pathway to help rid the cell of damaged mitochondria, and suggests that mechanisms for disposal of damaged mitochondria and possibly other toxic cellular components may be commonly targeted in such neurodegenerative diseases.
The Pex1 and Pex6 ATPases participate in peroxisome biogenesis. Mutations affecting these proteins are the most common cause of various generally fatal peroxisomal diseases. In a collaboration among the laboratories of Rapoport, Walz, and DiMaio/Baker, structures of the Pex1/Pex6 complex were determined in the presence of different nucleotides by cryo-electron microscopy (Blok et al., 2015). The structures support the hypothesis that the Pex1/Pex6 complex has a role in peroxisomal protein import analogous to that of another ATPase, p97, in ER-associated protein degradation.
Allied-Bristol Life Sciences, a joint venture between the university commercialization specialist Allied Minds and the US pharmaceutical company Bristol-Myers Squibb, is licensing research carried out by Malcolm Whitman on halofuginone, an active ingredient in blue evergreen hydrangea root. The Whitman Lab had showed several years ago that halofuginone could block the development of TH17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response (AAR) pathway. They subsequently showed that halofuginone binds glutamyl-prolyl-tRNA synthetase (EPRS), which inhibits prolyl-tRNA synthetase activity; this inhibition of EPRSunderlies the broad bioactivities of this family of natural product derivatives. Now, Allied-Bristol Life Sciences is hoping to use this research to develop drugs to treat multipes types of autoimmune diseases.
Current and recent members of the Van Vactor and Perrimon laboratories at HMS have created a transgenic resource to allow conditional analysis of in vivo functions for over 140 microRNA genes in Drosophila with spatial and temporal precision. This resource, just published in Nature Communications, represents a highly collaborative project that will open the door to a broad variety of novel functional screens. Using this toolkit to explore the landscape of regulatory function in muscle tissue, they discovered a dozen microRNAs required for the maintenance of flight muscle form and function, suggesting that post-transcriptional mechanisms may be vital for protecting muscle from degeneration.
Using a combination of live cell imaging and single cell genome sequencing (Look-Seq), the Pellman laboratory has defined a mechanism for a new mutational process in cancer and congenital disease called chromothripsis (Zhang et al., Nature, 2015). In chromothripsis there is massive rearrangement of typically one of a cell’s chromosomes, leaving the rest of the genome unaltered. By recreating chromothripsis in the laboratory, the group shows that it can originate from abnormal nuclear structures, common in cancer cells, called micronuclei. The findings illustrate the importance of nuclear architecture and integrity for the maintenance of genome stability. The work was done in collaboration with Matthew Meyerson’s laboratory (Dana-Farber Cancer Institute & Department of Pathology at Harvard Medical School).
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Alternative splicing (AS) contributes to the proteomic diversity. In the brain, it emerges as a pervasive mechanism that plays a crucial role in the regulation of neuron maturation and activity. Chromatin modifying enzymes, that impact chromatin structure and globally control specific gene expression programs, are also subject to AS. However, at molecular level, it is poorly understood how AS can affect enzyme substrate specificity. In a recent publication in Molecular Cell (Laurent B. et al., PMID 25684206), Shi lab shed light on how AS can switch the enzymatic activity of the histone demethylase LSD1. In neurons, AS generates LSD1+8a, a LSD1 isoform containing an additional exon of 4 amino-acids (E8a). LSD1 has been reported to repress gene expression by demethylating histone H3K4. In their study, the authors show that the LSD1+8a isoform does not have the intrinsic capability to demethylate H3K4. Instead, LSD1+8a mediates H3K9 demethylation, in collaboration with the SVIL protein, and activate gene expression at its target promoters. Moreover, LSD1+8a and SVIL knockdowns increase H3K9 methylation levels at their target genes and compromise neuronal differentiation. These findings highlight AS as a means by which LSD1 acquires selective substrate specificities (H3K9 vs H3K4) to differentially control specific gene expression programs in neurons.
Note: This Shi lab publication was commented in its related Molecular Cell issue (Shin J. et al., PMID 25794611).
Breathing is essential for survival, and under precise neural control. The vagus nerve is a major connection between lung and brain required for normal respiration. In a recent publication in Cell, the Liberles Lab used molecular and genetic approaches to deconstruct the sensory vagus nerve, identifying two small populations of sensory neurons that exert powerful and opposing effects on breathing. Genetically guided anatomical mapping using Cre/LoxP technology revealed that these neurons densely innervate the lung and send long-range projections to different stereotyped brainstem targets. Optogenetic stimulation of one neuron type (P2ry1) acutely silences respiration, trapping animals in a state of exhalation, while activating another (Npy2r) causes rapid and shallow breathing. Activating P2ry1 neurons had no effect on heart rate and gastric pressure, other essential vagus nerve functions. Thus, the vagus nerve contains genetically definable labeled lines with different anatomical connections and autonomic roles. Specific manipulation of breathing-control neurons electrically or pharmacologically may impact airway diseases like asthma or apnea.
Congratulations to Tobi Walter, who was chosen from a group of 894 eligible applicants to be one of 26 newly-minted Howard Hughes Medical Institute (HHMI) Investigators! HHMI investigators will receive the flexible support necessary to move their research in creative new directions. The initiative represents an investment in basic biomedical research of $153 million over the next five years.
The scientists represent 19 institutions from across the United States. The new HHMI investigators – which include three current HHMI early career scientists -- were selected for their individual scientific excellence.
HHMI will provide each investigator with his or her full salary, benefits, and a research budget over their initial five-year appointment. The Institute will also cover other expenses, including research space and the purchase of critical equipment. Their appointment may be renewed for additional five-year terms, each contingent on a successful scientific review.
HHMI encourages its investigators to push their research fields into new areas of inquiry. By employing scientists as HHMI investigators — rather than awarding them research grants — the Institute is guided by the principle of “people, not projects.” HHMI investigators have the freedom to explore and, if necessary, to change direction in their research. Moreover, they have support to follow their ideas through to fruition — even if that process takes many years.
The National Academy of Sciences recently announced the election of 84 new members and 21 foreign associates from 15 countries in recognition of their distinguished and continuing achievements in original research. Among this list is Fred Goldberg, Professor of Cell Biology. The National Academy of Sciences is a private, non-profit society of distinguished scholars. Established by an Act of Congress, signed by President Abraham Lincoln in 1863, the NAS is charged with providing independent, objective advice to the nation on matters related to science and technology. Scientists are elected by their peers to membership in the NAS for outstanding contributions to research. Congrats Fred!
The American Diabetes Association will present the Outstanding Scientific Achievement Award to Pere Puigserver, PhD. Supported by an unrestricted educational grant from Lilly USA, LLC, this prestigious award recognizes research in diabetes that demonstrates particular independence of thought and originality. Dr. Puigserver will be recognized with this honor at the Association’s 75th Scientific Sessions, taking place June 5-9, 2015, at the Boston Convention and Exhibition Center in Boston. Congrats Pere! For more information, click here.