PMID- 32229726
OWN - NLM
STAT- MEDLINE
DCOM- 20210202
LR  - 20240214
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 130
IP  - 7
DP  - 2020 Jul 1
TI  - Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and 
      cholesterol biosynthesis.
PG  - 3654-3670
LID - 132414 [pii]
LID - 10.1172/JCI132414 [doi]
AB  - Germinal center (GC) responses require B cells to respond to a dynamic set of 
      intercellular and microenvironmental signals that instruct B cell positioning, 
      differentiation, and metabolic reprogramming. RHO-associated 
      coiled-coil-containing protein kinase 2 (ROCK2), a serine-threonine kinase that 
      can be therapeutically targeted by ROCK inhibitors or statins, is a key 
      downstream effector of RHOA GTPases. Although RHOA-mediated pathways are emerging 
      as critical regulators of GC responses, the role of ROCK2 in B cells is unknown. 
      Here, we found that ROCK2 was activated in response to key T cell signals like 
      CD40 and IL-21 and that it regulated GC formation and maintenance. RNA-Seq 
      analyses revealed that ROCK2 controlled a unique transcriptional program in GC B 
      cells that promoted optimal GC polarization and cholesterol biosynthesis. ROCK2 
      regulated this program by restraining AKT activation and subsequently enhancing 
      FOXO1 activity. ATAC-Seq (assay for transposase-accessible chromatin with 
      high-throughput sequencing) and biochemical analyses revealed that the effects of 
      ROCK2 on cholesterol biosynthesis were instead mediated via a novel mechanism. 
      ROCK2 directly phosphorylated interferon regulatory factor 8 (IRF8), a crucial 
      mediator of GC responses, and promoted its interaction with sterol regulatory 
      element-binding transcription factor 2 (SREBP2) at key regulatory regions 
      controlling the expression of cholesterol biosynthetic enzymes, resulting in 
      optimal recruitment of SREBP2 at these sites. These findings thus uncover ROCK2 
      as a multifaceted and therapeutically targetable regulator of GC responses.
FAU - Ricker, Edd
AU  - Ricker E
AD  - Autoimmunity and Inflammation Program, Hospital for Special Surgery (HSS), New 
      York, New York, USA.
AD  - Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New 
      York, USA.
FAU - Chinenov, Yurii
AU  - Chinenov Y
AD  - David Z. Rosensweig Genomics Research Center.
FAU - Pannellini, Tania
AU  - Pannellini T
AD  - Research Division and.
AD  - Precision Medicine Laboratory, HSS, New York, New York, USA.
FAU - Flores-Castro, Danny
AU  - Flores-Castro D
AD  - Autoimmunity and Inflammation Program, Hospital for Special Surgery (HSS), New 
      York, New York, USA.
FAU - Ye, Chao
AU  - Ye C
AD  - Autoimmunity and Inflammation Program, Hospital for Special Surgery (HSS), New 
      York, New York, USA.
FAU - Gupta, Sanjay
AU  - Gupta S
AD  - Autoimmunity and Inflammation Program, Hospital for Special Surgery (HSS), New 
      York, New York, USA.
FAU - Manni, Michela
AU  - Manni M
AD  - Autoimmunity and Inflammation Program, Hospital for Special Surgery (HSS), New 
      York, New York, USA.
FAU - Liao, James K
AU  - Liao JK
AD  - Department of Medicine, University of Chicago, Chicago, Illinois, USA.
FAU - Pernis, Alessandra B
AU  - Pernis AB
AD  - Autoimmunity and Inflammation Program, Hospital for Special Surgery (HSS), New 
      York, New York, USA.
AD  - David Z. Rosensweig Genomics Research Center.
AD  - Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
LA  - eng
GR  - R01 AR070146/AR/NIAMS NIH HHS/United States
GR  - R01 HL136962/HL/NHLBI NIH HHS/United States
GR  - F31 CA196209/CA/NCI NIH HHS/United States
GR  - R01 AR064883/AR/NIAMS NIH HHS/United States
GR  - T32 AR071302/AR/NIAMS NIH HHS/United States
GR  - S10 OD019986/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (Interferon Regulatory Factors)
RN  - 0 (Srebf2 protein, mouse)
RN  - 0 (Sterol Regulatory Element Binding Protein 2)
RN  - 0 (interferon regulatory factor-8)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Rock2 protein, mouse)
RN  - EC 2.7.11.1 (rho-Associated Kinases)
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/cytology/*metabolism
MH  - Cell Line
MH  - Cholesterol/*biosynthesis/genetics
MH  - Forkhead Box Protein O1/genetics/metabolism
MH  - Germinal Center/cytology/*metabolism
MH  - Interferon Regulatory Factors/genetics/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Sterol Regulatory Element Binding Protein 2/genetics/metabolism
MH  - rho-Associated Kinases/genetics/*metabolism
PMC - PMC7324193
OTO - NOTNLM
OT  - Adaptive immunity
OT  - B cells
OT  - Immunology
COIS- Conflict of interest: ABP previously received an investigator-initiated research 
      grant from Kadmon Corporation for studies of SLE T cells.
EDAT- 2020/04/02 06:00
MHDA- 2021/02/03 06:00
PMCR- 2020/10/01
CRDT- 2020/04/02 06:00
PHST- 2019/08/07 00:00 [received]
PHST- 2020/03/24 00:00 [accepted]
PHST- 2020/04/02 06:00 [pubmed]
PHST- 2021/02/03 06:00 [medline]
PHST- 2020/04/02 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - 132414 [pii]
AID - 10.1172/JCI132414 [doi]
PST - ppublish
SO  - J Clin Invest. 2020 Jul 1;130(7):3654-3670. doi: 10.1172/JCI132414.