PMID- 35658015
OWN - NLM
STAT- MEDLINE
DCOM- 20220608
LR  - 20220906
IS  - 2470-9468 (Electronic)
IS  - 2470-9468 (Linking)
VI  - 7
IP  - 72
DP  - 2022 Jun 3
TI  - RNA exosome drives early B cell development via noncoding RNA processing 
      mechanisms.
PG  - eabn2738
LID - 10.1126/sciimmunol.abn2738 [doi]
AB  - B cell development is linked to successful V(D)J recombination, allowing B cell 
      receptor expression and ultimately antibody secretion for adaptive immunity. 
      Germline noncoding RNAs (ncRNAs) are produced at immunoglobulin (Ig) loci during 
      V(D)J recombination, but their function and posttranscriptional regulation are 
      incompletely understood. Patients with trichohepatoenteric syndrome, 
      characterized by RNA exosome pathway component mutations, exhibit lymphopenia, 
      thus demonstrating the importance of ncRNA surveillance in B cell development in 
      humans. To understand the role of RNA exosome in early B cell development in 
      greater detail, we generated mouse models harboring a B cell-specific cre allele 
      (Mb1(cre)), coupled to conditional inversion-deletion alleles of one RNA exosome 
      core component (Exosc3) or RNase catalytic subunits (Exosc10 or Dis3). We noticed 
      increased expression of RNA exosome subunits during V(D)J recombination, whereas 
      a B cell developmental blockade at the pro-B cell stage was observed in the 
      different knockout mice, overlapping with a lack of productive rearrangements of 
      VDJ genes at the Ig heavy chain (Igh). This unsuccessful recombination prevented 
      differentiation into pre-B cells, with accumulation of ncRNAs and up-regulation 
      of the p53 pathway. Introduction of a prearranged Igh VDJ allele partly rescued 
      the pre-B cell population in Dis3-deficient cells, although V-J recombination 
      defects were observed at Ig light chain kappa (Igkappa), preventing subsequent B cell 
      development. These observations demonstrated that the RNA exosome complex is 
      important for Igh and Igkappa recombination and establish the relevance of RNA 
      processing for optimal diversification at these loci during B cell development.
FAU - Laffleur, Brice
AU  - Laffleur B
AUID- ORCID: 0000-0003-2904-9345
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
FAU - Batista, Carolina R
AU  - Batista CR
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
FAU - Zhang, Wanwei
AU  - Zhang W
AUID- ORCID: 0000-0001-9949-1206
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
FAU - Lim, Junghyun
AU  - Lim J
AUID- ORCID: 0000-0002-5292-7487
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
FAU - Yang, Biao
AU  - Yang B
AUID- ORCID: 0000-0002-6002-3330
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
FAU - Rossille, Delphine
AU  - Rossille D
AUID- ORCID: 0000-0002-7892-9018
AD  - Universite of Rennes, INSERM, EFS Bretagne, CHU Rennes, UMR 1236, Rennes, France.
FAU - Wu, Lijing
AU  - Wu L
AUID- ORCID: 0000-0002-0736-9826
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
FAU - Estrella, Jerson
AU  - Estrella J
AUID- ORCID: 0000-0002-6770-6206
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
FAU - Rothschild, Gerson
AU  - Rothschild G
AUID- ORCID: 0000-0001-7622-9715
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
FAU - Pefanis, Evangelos
AU  - Pefanis E
AD  - Regeneron Pharmaceuticals, Tarrytown, New York, NY 10591, USA.
FAU - Basu, Uttiya
AU  - Basu U
AUID- ORCID: 0000-0002-0185-7052
AD  - Department of Microbiology and Immunology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY 10032, USA.
LA  - eng
GR  - R01 AI099195/AI/NIAID NIH HHS/United States
GR  - R01 AI134988/AI/NIAID NIH HHS/United States
GR  - R01 AI143897/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220603
PL  - United States
TA  - Sci Immunol
JT  - Science immunology
JID - 101688624
RN  - 0 (Immunoglobulin Heavy Chains)
RN  - 0 (RNA, Untranslated)
RN  - EC 3.1.- (Exoribonucleases)
RN  - EC 3.1.- (Exosome Multienzyme Ribonuclease Complex)
RN  - EC 3.1.13.- (EXOSC10 protein, human)
RN  - EC 3.1.13.- (Exosc10 protein, mouse)
SB  - IM
CIN - Nat Rev Immunol. 2022 Aug;22(8):462-463. PMID: 35773353
MH  - Animals
MH  - *B-Lymphocytes
MH  - Exoribonucleases/genetics/metabolism
MH  - *Exosome Multienzyme Ribonuclease Complex/genetics/metabolism
MH  - Humans
MH  - Immunoglobulin Heavy Chains/genetics
MH  - Mice
MH  - RNA Processing, Post-Transcriptional
MH  - RNA, Untranslated/genetics
MH  - V(D)J Recombination/genetics
PMC - PMC9357289
MID - NIHMS1824326
COIS- COMPETING INTERESTS The authors declare no competing interests.
EDAT- 2022/06/04 06:00
MHDA- 2022/06/09 06:00
PMCR- 2022/08/07
CRDT- 2022/06/03 14:04
PHST- 2022/06/03 14:04 [entrez]
PHST- 2022/06/04 06:00 [pubmed]
PHST- 2022/06/09 06:00 [medline]
PHST- 2022/08/07 00:00 [pmc-release]
AID - 10.1126/sciimmunol.abn2738 [doi]
PST - ppublish
SO  - Sci Immunol. 2022 Jun 3;7(72):eabn2738. doi: 10.1126/sciimmunol.abn2738. Epub 
      2022 Jun 3.