A protease-independent function for SPPL3 in NFAT activation

Stefanie L. Makowski, Zhaoquan Wang, Joel L. Pomerantz

Research output: Contribution to journalArticlepeer-review


The signal peptide peptidase (SPP)-related intramembrane aspartyl proteases are a homologous group of polytopic membrane proteins, some of which function in innate or adaptive immunity by cleaving proteins involved in antigen presentation or intracellular signaling. Signal peptide peptidase-like 3 (SPPL3) is a poorly characterized endoplasmic reticulum (ER)-localized member of this family, with no validated cellular substrates. We report here the isolation of SPPL3 in a screen for activators of NFAT, a transcription factor that controls lymphocyte development and function. We find that SPPL3 is required downstream of T cell receptor engagement for maximal Ca2+ influx and NFAT activation. Surprisingly, the proteolytic activity of SPPL3 is not required for its role in this pathway. SPPL3 enhances the signal-induced association of stromal interaction molecule 1 (STIM1) and Orai1 and is even required for the full activity of constitutively active STIM1 variants that bind Orai1 independently of ER Ca2+ release. SPPL3 associates with STIM1 through at least two independent domains, the transmembrane region and the CRAC activation domain (CAD), and can promote the association of the STIM1 CAD with Orai1. Our results assign a function in lymphocyte signaling to SPPL3 and highlight the emerging importance of nonproteolytic functions for members of the intramembrane aspartyl protease family.

Original languageEnglish (US)
Pages (from-to)451-467
Number of pages17
JournalMolecular and cellular biology
Issue number2
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'A protease-independent function for SPPL3 in NFAT activation'. Together they form a unique fingerprint.

Cite this