SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production

Friedmann, Elena; Hauben, Ehud; Maylandt, K.; Schleeger, Simone; Vreugde, Sarah; Lichtenthaler, Stefan F.; Kuhn, Peer‐Hendrik; Stauffer, Daniela; Rovelli, Giorgio; Martoglio, Bruno

doi:10.1038/ncb1440

Cited by 179 publications

(223 citation statements)

References 32 publications

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“…Mass spectrometry revealed that rhomboid proteolysis is notably site-specific, in contrast to other intramembrane proteases (Fraering et al, 2004; Fluhrer et al, 2006; Friedmann et al, 2006; Sato et al, 2006). In fact, cleavage of the Drosophila EGF ligand Spitz always proceeded between the first two residues (AS) of its TM segment even with eight diverse rhomboid proteases and in bacterial, insect and human cells (and different organelles) that harbor lipid composition differences (Fast, 1966) (Figure 1A, also see Figure 1—figure supplement 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Intensively studied is γ-secretase, an aspartyl intramembrane protease that releases signaling domains from the membrane, including the intracellular domains of the Notch receptor and the amyloid-β precursor protein (APP) implicated in Alzheimer's disease (De Strooper et al, 1998, 1999; Wolfe et al, 1999). Homologous signal peptide peptidases function in immunity by liberating signaling domains of TNFα and FasL (Fluhrer et al, 2006; Friedmann et al, 2006; Kirkin et al, 2007). Site-2 proteases are metalloenzymes that release transcription factors from the membrane to regulate membrane biogenesis and stress responses in diverse organisms from bacterial pathogens to man (Rawson et al, 1997; Makinoshima and Glickman, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Moin

Urban

2012

eLife

119

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Rhomboid proteases reside within cellular membranes, but the advantage of this unusual environment is unclear. We discovered membrane immersion allows substrates to be identified in a fundamentally-different way, based initially upon exposing ‘masked’ conformational dynamics of transmembrane segments rather than sequence-specific binding. EPR and CD spectroscopy revealed that the membrane restrains rhomboid gate and substrate conformation to limit proteolysis. True substrates evolved intrinsically-unstable transmembrane helices that both become unstructured when not supported by the membrane, and facilitate partitioning into the hydrophilic, active-site environment. Accordingly, manipulating substrate and gate dynamics in living cells shifted cleavage sites in a manner incompatible with extended sequence binding, but correlated with a membrane-and-helix-exit propensity scale. Moreover, cleavage of diverse non-substrates was provoked by single-residue changes that destabilize transmembrane helices. Membrane immersion thus bestows rhomboid proteases with the ability to identify substrates primarily based on reading their intrinsic transmembrane dynamics.DOI: http://dx.doi.org/10.7554/eLife.00173.001

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Moin

Urban

2012

eLife

119

View full text Add to dashboard Cite

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“…Two recent publications report TNFa intramembrane cleavage by SPPL2a and SPPL2b, 36,37 which triggers expression of the pro-inflammatory cytokine interleukin-12 (IL-12) by activated human dendritic cells. 37 Together with our data on FasL processing by SPPL2a, these results indicate an emerging important role of SPPLs in RIP of TNF family members.…”

Section: Discussionmentioning

confidence: 99%

“…Several transmembrane proteins are subjected to intramembrane proteolysis, as a result of which the ICD is released for signaling to the nucleus 31,37 (also see references therein). Our findings of a similar FasL RIP by ADAM10 and SPPL2a prompted us to investigate whether the FasL ICD (liberated by SPPL2a cleavage) could translocate to the nucleus and influence gene transcription.…”

Section: Discussionmentioning

confidence: 99%

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Cahuzac²,

et al. 2007

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Fas ligand (FasL) is a type II transmembrane protein belonging to the tumor necrosis factor family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. The cell deathinducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL. The fate of the remaining membrane-anchored N-terminal part of the FasL molecule has not been determined. Here we show that post-translational processing of overexpressed and endogenous FasL in T-cells by the disintegrin and metalloprotease ADAM10 generates a 17-kDa N-terminal fragment, which lacks the receptor-binding extracellular domain. This FasL remnant is membrane anchored and further processed by SPPL2a, a member of the signal peptide peptidaselike family of intramembrane-cleaving proteases. SPPL2a cleavage liberates a smaller and highly unstable fragment mainly containing the intracellular FasL domain (FasL ICD). We show that this fragment translocates to the nucleus and is capable of inhibiting gene transcription. With ADAM10 and SPPL2a we have identified two proteases implicated in FasL processing and release of the FasL ICD, which has been shown to be important for retrograde FasL signaling.

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“…Two of these genes in particular are worth noting. NOD1 and SPPL2A both play an important role in the immune response and the development of inflammatory disease 37,38 and are therefore plausible candidate risk genes for PE and CVD.…”

Section: Discussionmentioning

confidence: 99%

Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease

et al. 2011

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Preeclampsia (PE) is a serious complication of pregnancy, which is highly correlated with later life cardiovascular disease (CVD). Many risk factors are common for both diseases, but the contribution of shared genes remains to be determined. In this study, we used an integrative strategy to assess lipid traits as risk factors for PE and CVD by whole genome transcriptional profiling performed on Norwegian decidua basalis tissues (N¼95) from preeclamptic and normal pregnancies and on blood lymphocytes (N¼1240) from the San Antonio Family Heart Study (SAFHS). Among 222 genes that were differentially expressed (false discovery rate (FDR) P-value o0.05) between the PE, cases and controls, we found one gene, ACOX2 (acyl-coenzyme A oxidase 2, branched chain), that was downregulated in PE whose transcription was also inversely correlated with triglyceride levels (P¼5.6Â10 À7 ; FDR P-value¼0.0002) in SAFHS. We further report associations between SNPs in the ACOX2 gene and the transcription level (P-value¼0.0045) of the gene, as well as with triglyceride levels (P-value¼0.0051). ACOX2 is involved in bile acid production, a process that has been associated with both oxidative stress and regulation of triglyceride levels. Oxidative stress and increased triglyceride levels are known risk factors for CVD and both have also been associated with PE. Our results suggest that downregulation of ACOX2 is a shared risk factor for PE and CVD.

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SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production

Cited by 179 publications

References 32 publications

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease

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