Autophagy and proteasome interconnect to coordinate cross-presentation through MHC class I pathway in B cells.
Cross-presentation of exogenous protein antigens by B cells through the major histocompatibility complex (MHC) class I pathway in lymphoid malignancies, and transplant setting has been recognised as an important mediator of immune pathogenesis and T cell-mediated immune regulation. However, the precise mechanism of cross-presentation of exogenous antigens in B cells has remained unresolved. Here we have delineated a novel pathway for cross-presentation in B cells, which involves synergistic cooperation of the proteasome and autophagy. After endocytosis, protein antigen is processed through an autophagy- and proteasome-dependent pathway and CD8+T-cell epitopes are loaded onto MHC class I molecules within the autophagolysomal compartment rather than the conventional secretory pathway, which requires transporters associated with antigen processing-dependent transport. Interestingly, this cross-presentation was critically dependent on valosin-containing protein (VCP)/p97 ATPase through its participation in autophagy. Loss of VCP/p97 ATPase was coincident with accumulation of LC3-II and marked reduction in antigen presentation. These observations provide unique insight on how the autophagy and proteasomal degradation systems interconnect to coordinate MHC class I-restricted cross-presentation in B cells.
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Vijayendra
V
Dasari
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Sweera
S
Rehan
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Siok-Keen
SK
Tey
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Mark J
MJ
Smyth
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Corey
C
Smith
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Rajiv
R
Khanna
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000276:immunology*; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology*; D003587:Cytomegalovirus / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D000074405:Valosin Containing Protein / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000071183:Autophagy-Related Proteins; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins; C477327:transporter associated with antigen processing (TAP); D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex; D000074405:Valosin Containing Protein