title: The microtubule regulator stathmin is an endogenous protein agonist for TLR3.
abstract: TLR3 recognizes dsRNAs and is considered of key importance to antiviral host-defense responses. TLR3 also triggers neuroprotective responses in astrocytes and controls the growth of axons and neuronal progenitor cells, suggesting additional roles for TLR3-mediated signaling in the CNS. This prompted us to search for alternative, CNS-borne protein agonists for TLR3. A genome-scale functional screening of a transcript library from brain tumors revealed that the microtubule regulator stathmin is an activator of TLR3-dependent signaling in astrocytes, inducing the same set of neuroprotective factors as the known TLR3 agonist polyinosinic:polycytidylic acid. This activity of stathmin crucially depends on a long, negatively charged alpha helix in the protein. Colocalization of stathmin with TLR3 on astrocytes, microglia, and neurons in multiple sclerosis-affected human brain indicates that as an endogenous TLR3 agonist, stathmin may fulfill previously unsuspected regulatory roles during inflammation and repair in the adult CNS.
authors.affiliation: Department of Biomedical Research, TNO Quality of Life, Delta Crystallon, Leiden, The Netherlands.
authors.forename: Malika
authors.initials: M
authors.lastname: Bsibsi
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Bajramovic
authors.forename: Mario H J
authors.initials: MH
authors.lastname: Vogt
authors.forename: Eveline
authors.initials: E
authors.lastname: van Duijvenvoorden
authors.forename: Aabed
authors.initials: A
authors.lastname: Baghat
authors.forename: Carla
authors.initials: C
authors.lastname: Persoon-Deen
authors.forename: Frans
authors.initials: F
authors.lastname: Tielen
authors.forename: Richard
authors.initials: R
authors.lastname: Verbeek
authors.forename: Inge
authors.initials: I
authors.lastname: Huitinga
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Alexander
authors.initials: A
authors.lastname: Kros
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Gerritsen
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
authors.forename: Johannes M
authors.initials: JM
authors.lastname: van Noort
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D015723:Gene Library; D006801:Humans; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D008870:Microtubules / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D050777:Stathmin / Q000276:immunology* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000276:immunology* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D050777:Stathmin; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3