PMID- 35324997
OWN - NLM
STAT- MEDLINE
DCOM- 20220422
LR  - 20220531
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 18
IP  - 3
DP  - 2022 Mar
TI  - The Cdkn2a gene product p19 alternative reading frame (p19ARF) is a critical 
      regulator of IFNbeta-mediated Lyme arthritis.
PG  - e1010365
LID - 10.1371/journal.ppat.1010365 [doi]
LID - e1010365
AB  - Type I interferon (IFN) has been identified in patients with Lyme disease, and 
      its abundant expression in joint tissues of C3H mice precedes development of Lyme 
      arthritis. Forward genetics using C3H mice with severe Lyme arthritis and C57BL/6 
      (B6) mice with mild Lyme arthritis identified the Borrelia burgdorferi 
      arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) as a regulator of B. 
      burgdorferi-induced IFNbeta expression and Lyme arthritis severity. B6 mice 
      introgressed with the C3H allele for Bbaa1 (B6.C3-Bbaa1 mice) displayed increased 
      severity of arthritis, which is initiated by myeloid lineage cells in joints. 
      Using advanced congenic lines, the physical size of the Bbaa1 interval has been 
      reduced to 2 Mbp, allowing for identification of potential genetic regulators. 
      Small interfering RNA (siRNA)-mediated silencing identified Cdkn2a as the gene 
      responsible for Bbaa1 allele-regulated induction of IFNbeta and IFN-stimulated genes 
      (ISGs) in bone marrow-derived macrophages (BMDMs). The Cdkn2a-encoded p19 
      alternative reading frame (p19ARF) protein regulates IFNbeta induction in BMDMs as 
      shown by siRNA silencing and overexpression of ARF. In vivo studies demonstrated 
      that p19ARF contributes to joint-specific induction of IFNbeta and arthritis 
      severity in B. burgdorferi-infected mice. p19ARF regulates B. burgdorferi-induced 
      IFNbeta in BMDMs by stabilizing the tumor suppressor p53 and sequestering the 
      transcriptional repressor BCL6. Our findings link p19ARF regulation of p53 and 
      BCL6 to the severity of IFNbeta-induced Lyme arthritis in vivo and indicate 
      potential novel roles for p19ARF, p53, and BCL6 in Lyme disease and other IFN 
      hyperproduction syndromes.
FAU - Li, Jinze
AU  - Li J
AUID- ORCID: 0000-0001-9108-6927
AD  - Department of Pathology, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Ma, Ying
AU  - Ma Y
AD  - Department of Pathology, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Paquette, Jackie K
AU  - Paquette JK
AD  - Department of Pathology, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Richards, Amanda C
AU  - Richards AC
AD  - Department of Pathology, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Mulvey, Matthew A
AU  - Mulvey MA
AD  - Department of Pathology, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Zachary, James F
AU  - Zachary JF
AD  - Department of Veterinary Pathobiology, University of Illinois at 
      Urbana-Champaign, Urbana, Illinois, United States of America.
FAU - Teuscher, Cory
AU  - Teuscher C
AUID- ORCID: 0000-0002-9236-8843
AD  - Department of Medicine, Vermont Center for Immunology and Infectious Diseases, 
      Larner College of Medicine, The University of Vermont, Burlington, Vermont, 
      United States of America.
FAU - Weis, Janis J
AU  - Weis JJ
AUID- ORCID: 0000-0001-7214-5987
AD  - Department of Pathology, University of Utah, Salt Lake City, Utah, United States 
      of America.
LA  - eng
GR  - R01 GM134331/GM/NIGMS NIH HHS/United States
GR  - T32 AI055434/AI/NIAID NIH HHS/United States
GR  - R21 NS095007/NS/NINDS NIH HHS/United States
GR  - R01 NS097596/NS/NINDS NIH HHS/United States
GR  - R01 AI032223/AI/NIAID NIH HHS/United States
GR  - R01 AR043521/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220324
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Cdkn2a protein, mouse)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 77238-31-4 (Interferon-beta)
SB  - IM
MH  - Animals
MH  - *Arthritis/genetics
MH  - Borrelia burgdorferi
MH  - *Cyclin-Dependent Kinase Inhibitor p16/genetics
MH  - Genes, p16
MH  - Interferon-beta/genetics/metabolism
MH  - *Lyme Disease/genetics
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mice, Inbred C57BL
MH  - RNA, Small Interfering
MH  - Reading Frames
MH  - Tumor Suppressor Protein p53/genetics
PMC - PMC8946740
COIS- The authors have declared that no competing interests exist.
EDAT- 2022/03/25 06:00
MHDA- 2022/04/23 06:00
PMCR- 2022/03/24
CRDT- 2022/03/24 17:25
PHST- 2021/09/14 00:00 [received]
PHST- 2022/02/11 00:00 [accepted]
PHST- 2022/03/24 17:25 [entrez]
PHST- 2022/03/25 06:00 [pubmed]
PHST- 2022/04/23 06:00 [medline]
PHST- 2022/03/24 00:00 [pmc-release]
AID - PPATHOGENS-D-21-01880 [pii]
AID - 10.1371/journal.ppat.1010365 [doi]
PST - epublish
SO  - PLoS Pathog. 2022 Mar 24;18(3):e1010365. doi: 10.1371/journal.ppat.1010365. 
      eCollection 2022 Mar.