HN1L/JPT2: A signaling protein that connects NAADP generation to Ca2+ microdomain formation

  • Sci Signal. 2021 Mar 23;14(675):eabd5647. doi: 10.1126/scisignal.abd5647.
Hannes G Roggenkamp  1 ,  Imrankhan Khansahib  1 ,  Lola C Hernandez C  1 ,  Yunpeng Zhang  1 ,  Dmitri Lodygin  2 ,  Aileen Krüger  1 ,  Feng Gu  1 ,  Franziska Möckl  1 ,  Anke Löhndorf  1 ,  Valerie Wolters  1 ,  Daniel Woike  1 ,  Anette Rosche  1 ,  Andreas Bauche  1 ,  Daniel Schetelig  3 ,  René Werner  3 ,  Hartmut Schlüter  4 ,  Antonio V Failla  5 ,  Chris Meier  6 ,  Ralf Fliegert  1 ,  Timothy F Walseth  7 ,  Alexander Flügel  2 ,  Björn-Philipp Diercks  8 ,  Andreas H Guse  8
Affiliations
  • 1. The Ca Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 2. Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre Göttingen, 37075 Göttingen, Germany.
  • 3. Department of Computational Neuroscience, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 4. Mass Spectrometric Proteomics Group, Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 5. Microscopy Imaging Facility (UMIF), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 6. Organic Chemistry, University of Hamburg, 20146 Hamburg, Germany.
  • 7. Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455-0217, USA.
  • 8. The Ca Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. [email protected] [email protected].
PMID: 33758062 DOI: 10.1126/scisignal.abd5647
Abstract

NAADP-evoked CA2+ release through type 1 ryanodine receptors (RYR1) is a major mechanism underlying the earliest signals in T cell activation, which are the formation of CA2+ microdomains. In our characterization of the molecular machinery underlying NAADP action, we identified an NAADP-binding protein, called hematological and neurological expressed 1-like protein (HN1L) [also known as Jupiter microtubule-associated homolog 2 (JPT2)]. Gene deletion of Hn1l/Jpt2 in human Jurkat and primary rat T cells resulted in decreased numbers of initial CA2+ microdomains and delayed the onset and decreased the amplitude of global CA2+ signaling. Photoaffinity labeling demonstrated direct binding of NAADP to recombinant HN1L/JPT2. T cell receptor/CD3-dependent coprecipitation of HN1L/JPT2 with RYRs and colocalization of these proteins suggest that HN1L/JPT2 connects NAADP formation with the activation of RYR channels within the first seconds of T cell activation. Thus, HN1L/JPT2 enables NAADP to activate CA2+ release from the endoplasmic reticulum through RYR.