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.

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