title: Selective modulation of autophagy, innate immunity, and adaptive immunity by small molecules.
abstract: Autophagy is an evolutionarily conserved catabolic process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. Autophagy acts at the intersection of pathways involved in cellular stress, host defense, and modulation of inflammatory and immune responses; however, the details of how the autophagy network intersects with these processes remain largely undefined. Given the role of autophagy in several human diseases, it is important to determine the extent to which modulators of autophagy also modify inflammatory or immune pathways and whether it is possible to modulate a subset of these pathways selectively. Here, we identify small-molecule inducers of basal autophagy (including several FDA-approved drugs) and characterize their effects on IL-1β production, autophagic engulfment and killing of intracellular bacteria, and development of Treg, TH17, and TH1 subsets from naïve T cells. Autophagy inducers with distinct, selective activity profiles were identified that reveal the functional architecture of connections between autophagy, and innate and adaptive immunity. In macrophages from mice bearing a conditional deletion of the essential autophagy gene Atg16L1, the small molecules inhibit IL-1β production to varying degrees suggesting that individual compounds may possess both autophagy-dependent and autophagy-independent activity on immune pathways. The small molecule autophagy inducers constitute useful probes to test the contributions of autophagy-related pathways in diseases marked by impaired autophagy or elevated IL-1β and to test novel therapeutic hypotheses.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA.|Broad Institute of Harvard and MIT, Cambridge, MA.
authors.forename: Stanley Y
authors.initials: SY
authors.lastname: Shaw
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA.
authors.forename: Khoa
authors.initials: K
authors.lastname: Tran
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Castoreno
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Peloquin
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA.
authors.forename: Kara G
authors.initials: KG
authors.lastname: Lassen
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Khor
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA.|Dept. Of Chemistry and Chemical Biology, Harvard University, Cambridge, MA.
authors.forename: Leslie N
authors.initials: LN
authors.lastname: Aldrich
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA.
authors.forename: Pauline H
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Dept. Of Chemistry and Chemical Biology, Harvard University, Cambridge, MA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA.
authors.forename: Petric
authors.initials: P
authors.lastname: Kuballa
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA.|Dept. Of Chemistry and Chemical Biology, Harvard University, Cambridge, MA.|Howard Hughes Medical Institute, Cambridge, MA.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA.|Broad Institute of Harvard and MIT, Cambridge, MA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000276:immunology; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D007155:Immunologic Factors; D053583:Interleukin-1beta; D054852:Small Molecule Libraries