Unexpected role for the immunoproteasome subunit LMP2 in antiviral humoral and innate immune responses.
Proteasomes are multisubunit proteases that initiate degradation of many Ags presented by MHC class I molecules. Vertebrates express alternate forms of each of the three catalytic proteasome subunits: standard subunits, and immunosubunits, which are constitutively expressed by APCs and are induced in other cell types by exposure to cytokines. The assembly of mixed proteasomes containing standard subunits and immunosubunits is regulated in a tissue specific manner. In this study, we report that the presence of mixed proteasomes in immune cells in LMP2(-/-) mice compromises multiple components that contribute to the generation of antiviral Ab responses, including splenic B cell numbers, survival and function of adoptively transferred B cells, Th cell function, and dendritic cell secretion of IL-6, TNF-alpha, IL-1beta, and type I IFNs. These defects did not result from compromised overall protein degradation, rather they were associated with altered NF-kappaB activity. These findings demonstrate an important role for immunoproteasomes in immune cell function beyond their contribution to Ag processing.
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Scott E
SE
Hensley
Damien
D
Zanker
Brian P
BP
Dolan
Alexandre
A
David
Heather D
HD
Hickman
Alan C
AC
Embry
Cara N
CN
Skon
Kristie M
KM
Grebe
Thomas A
TA
Griffin
Weisan
W
Chen
Jack R
JR
Bennink
Jonathan W
JW
Yewdell
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000378:metabolism; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000821:virology; D007113:Immunity, Innate / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D000914:Antibodies, Viral; D016328:NF-kappa B; D021122:Protein Subunits; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex