PMID- 35446348
OWN - NLM
STAT- MEDLINE
DCOM- 20220425
LR  - 20220716
IS  - 1540-8140 (Electronic)
IS  - 0021-9525 (Print)
IS  - 0021-9525 (Linking)
VI  - 221
IP  - 6
DP  - 2022 Jun 6
TI  - Antigen-derived peptides engage the ER stress sensor IRE1alpha to curb dendritic cell 
      cross-presentation.
LID - 10.1083/jcb.202111068 [doi]
LID - e202111068
AB  - Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based 
      epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides 
      that enter the endoplasmic reticulum (ER), bind to major histocompatibility type 
      I (MHC-I) protein complexes, and are transported to the cell surface for 
      cross-presentation. DCs can exhibit activation of the ER stress sensor IRE1alpha 
      without ER stress, but the underlying mechanism remains obscure. Here, we show 
      that antigen-derived hydrophobic peptides can directly engage ER-resident IRE1alpha, 
      masquerading as unfolded proteins. IRE1alpha activation depletes MHC-I heavy-chain 
      mRNAs through regulated IRE1alpha-dependent decay (RIDD), curtailing antigen 
      cross-presentation. In tumor-bearing mice, IRE1alpha disruption increased MHC-I 
      expression on tumor-infiltrating DCs and enhanced recruitment and activation of 
      CD8+ T cells. Moreover, IRE1alpha inhibition synergized with anti-PD-L1 antibody 
      treatment to cause tumor regression. Our findings identify an unexpected 
      cell-biological mechanism of antigen-driven IRE1alpha activation in DCs, revealing 
      translational potential for cancer immunotherapy.
CI  - (c) 2022 Genentech, Inc.
FAU - Guttman, Ofer
AU  - Guttman O
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Le Thomas, Adrien
AU  - Le Thomas A
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Marsters, Scot
AU  - Marsters S
AUID- ORCID: 0000-0002-8517-0994
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Lawrence, David A
AU  - Lawrence DA
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Gutgesell, Lauren
AU  - Gutgesell L
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Zuazo-Gaztelu, Iratxe
AU  - Zuazo-Gaztelu I
AUID- ORCID: 0000-0002-0800-2639
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Harnoss, Jonathan M
AU  - Harnoss JM
AUID- ORCID: 0000-0002-4272-5769
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Haag, Simone M
AU  - Haag SM
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Murthy, Aditya
AU  - Murthy A
AUID- ORCID: 0000-0002-6130-9568
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Strasser, Geraldine
AU  - Strasser G
AUID- ORCID: 0000-0002-8074-8128
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Modrusan, Zora
AU  - Modrusan Z
AD  - Departments of Microchemistry, Proteomics and Lipidomics, Genentech, South San 
      Francisco, CA.
FAU - Wu, Thomas
AU  - Wu T
AUID- ORCID: 0000-0003-4505-4531
AD  - Departments of Oncology Bioinformatics, Genentech, South San Francisco, CA.
FAU - Mellman, Ira
AU  - Mellman I
AUID- ORCID: 0000-0002-6132-7299
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
FAU - Ashkenazi, Avi
AU  - Ashkenazi A
AUID- ORCID: 0000-0002-6890-4589
AD  - Departments of Cancer Immunology, Genentech, South San Francisco, CA.
LA  - eng
PT  - Journal Article
DEP - 20220421
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Peptides)
RN  - EC 2.7.11.1 (Ern1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
SB  - IM
CIN - J Cell Biol. 2022 Jun 6;221(6):. PMID: 35544036
MH  - Animals
MH  - Antigen Presentation
MH  - Antigens, Neoplasm/immunology
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - *Cross-Priming
MH  - *Dendritic Cells/immunology
MH  - *Endoplasmic Reticulum Stress
MH  - *Endoribonucleases/metabolism
MH  - Histocompatibility Antigens Class I/metabolism
MH  - Mice
MH  - *Neoplasms/immunology/metabolism
MH  - Peptides/metabolism
MH  - *Protein Serine-Threonine Kinases/metabolism
PMC - PMC9036094
EDAT- 2022/04/22 06:00
MHDA- 2022/04/26 06:00
PMCR- 2022/04/21
CRDT- 2022/04/21 12:15
PHST- 2021/11/19 00:00 [received]
PHST- 2022/02/23 00:00 [revised]
PHST- 2022/03/31 00:00 [accepted]
PHST- 2022/04/21 12:15 [entrez]
PHST- 2022/04/22 06:00 [pubmed]
PHST- 2022/04/26 06:00 [medline]
PHST- 2022/04/21 00:00 [pmc-release]
AID - 213173 [pii]
AID - jcb.202111068 [pii]
AID - 10.1083/jcb.202111068 [doi]
PST - ppublish
SO  - J Cell Biol. 2022 Jun 6;221(6):e202111068. doi: 10.1083/jcb.202111068. Epub 2022 
      Apr 21.