The microtubule regulator stathmin is an endogenous protein agonist for TLR3.
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.
Bsibsi
Malika
M
Department of Biomedical Research, TNO Quality of Life, Delta Crystallon, Leiden, The Netherlands.
Bajramovic
Jeffrey J
JJ
Vogt
Mario H J
MH
van Duijvenvoorden
Eveline
E
Baghat
Aabed
A
Persoon-Deen
Carla
C
Tielen
Frans
F
Verbeek
Richard
R
Huitinga
Inge
I
Ryffel
Bernhard
B
Kros
Alexander
A
Gerritsen
Wouter H
WH
Amor
Sandra
S
van Noort
Johannes M
JM
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
D034741:RNA, Small Interfering; D050777:Stathmin; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3