Centrosome-intrinsic mechanisms modulate centrosome integrity during fever.
The centrosome is critical for cell division, ciliogenesis, membrane trafficking, and immunological synapse function. The immunological synapse is part of the immune response, which is often accompanied by fever/heat stress (HS). Here we provide evidence that HS causes deconstruction of all centrosome substructures primarily through degradation by centrosome-associated proteasomes. This renders the centrosome nonfunctional. Heat-activated degradation is centrosome selective, as other nonmembranous organelles (midbody, kinetochore) and membrane-bounded organelles (mitochondria) remain largely intact. Heat-induced centrosome inactivation was rescued by targeting Hsp70 to the centrosome. In contrast, Hsp70 excluded from the centrosome via targeting to membranes failed to rescue, as did chaperone inactivation. This indicates that there is a balance between degradation and chaperone rescue at the centrosome after HS. This novel mechanism of centrosome regulation during fever contributes to immunological synapse formation. Heat-induced centrosome inactivation is a physiologically relevant event, as centrosomes in leukocytes of febrile patients are disrupted.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
Anastassiia
A
Vertii
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
Wendy
W
Zimmerman
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
Maria
M
Ivshina
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605 stephen.doxsey@umassmed.edu.
Stephen
S
Doxsey
D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D005334:Fever / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism; D018386:Kinetochores / Q000378:metabolism / Q000502:physiology; D007962:Leukocytes / Q000473:pathology / Q000648:ultrastructure*; D059748:Proteolysis; D013315:Stress, Psychological / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins