Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis
| Autor: | Edd Ricker, Sanjay Gupta, Danny Flores-Castro, Chao Ye, Michela Manni, Tania Pannellini, Alessandra B. Pernis, James K. Liao, Yurii Chinenov |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
RHOA Mice Transgenic Cell Line 03 medical and health sciences Mice 0302 clinical medicine Animals Protein kinase A Transcription factor Protein kinase B Serine/threonine-specific protein kinase B-Lymphocytes rho-Associated Kinases CD40 biology Chemistry Forkhead Box Protein O1 Germinal center General Medicine Germinal Center Cell biology 030104 developmental biology Cholesterol 030220 oncology & carcinogenesis Interferon Regulatory Factors biology.protein IRF8 Proto-Oncogene Proteins c-akt Sterol Regulatory Element Binding Protein 2 Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|