Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation.
T follicular helper cells (Tfh) are critical for the longevity and quality of antibody-mediated protection against infection. Yet few signaling pathways have been identified to be unique solely to Tfh development. ROQUIN is a post-transcriptional repressor of T cells, acting through its ROQ domain to destabilize mRNA targets important for Th1, Th17, and Tfh biology. Here, we report that ROQUIN has a paradoxical function on Tfh differentiation mediated by its RING domain: mice with a T cell-specific deletion of the ROQUIN RING domain have unchanged Th1, Th2, Th17, and Tregs during a T-dependent response but show a profoundly defective antigen-specific Tfh compartment. ROQUIN RING signaling directly antagonized the catalytic α1 subunit of adenosine monophosphate-activated protein kinase (AMPK), a central stress-responsive regulator of cellular metabolism and mTOR signaling, which is known to facilitate T-dependent humoral immunity. We therefore unexpectedly uncover a ROQUIN-AMPK metabolic signaling nexus essential for selectively promoting Tfh responses.
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Roybel R
RR
Ramiscal
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Ian A
IA
Parish
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Robert S
RS
Lee-Young
Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Jeffrey J
JJ
Babon
Department of Physiology, Goodman Cancer Research Centre, McGill University, Montreal, Canada.
Julianna
J
Blagih
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Alvin
A
Pratama
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Jaime
J
Martin
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Naomi
N
Hawley
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Jean Y
JY
Cappello
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Pablo F
PF
Nieto
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Julia I
JI
Ellyard
Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Nadia J
NJ
Kershaw
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Rebecca A
RA
Sweet
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.|Immunology Division, Garvan Institute of Medical Research, Sydney, Australia.
Christopher C
CC
Goodnow
Department of Physiology, Goodman Cancer Research Centre, McGill University, Montreal, Canada.
Russell G
RG
Jones
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.|Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia.
Mark A
MA
Febbraio
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Carola G
CG
Vinuesa
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Vicki
V
Athanasopoulos
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D051379:Mice; D017384:Sequence Deletion; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D055372:AMP-Activated Protein Kinases
AMPK; ROQUIN; T follicular helper cell; cell biology; germinal center; immunology; mTOR; mouse; stress granule