A γ-secretase-like intramembrane cleavage of TNFα by the GxGD aspartyl protease SPPL2b
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig Maximilians University, 80336 Munich, Germany. Nature Cell Biology
(Impact Factor: 19.68).
09/2006; 8(8):894-6. DOI: 10.1038/ncb1450
Gamma-secretase and signal peptide peptidase (SPP) are unusual GxGD aspartyl proteases, which mediate intramembrane proteolysis. In addition to SPP, a family of SPP-like proteins (SPPLs) of unknown function has been identified. We demonstrate that SPPL2b utilizes multiple intramembrane cleavages to liberate the intracellular domain of tumor necrosis factor alpha (TNFalpha) into the cytosol and the carboxy-terminal counterpart into the extracellular space. These findings suggest common principles for regulated intramembrane proteolysis by GxGD aspartyl proteases.
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Available from: Regina Fluhrer
- "The intramembrane protease Signal-peptide-peptidase-like 2a (SPPL2a) resides in lysosomes and late endosomes  and has been implicated in the processing of type 2 transmembrane proteins  including TNFa  , the Fas ligand , the Bri2 protein  and the invariant chain (CD74) of the MHCII complex . Among these, only the latter has been confirmed in vivo. "
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ABSTRACT: The invariant chain (CD74) mediates targeting of the MHCII complex to endosomal compartments, where CD74 undergoes degradation allowing MHCII to acquire peptides. We demonstrated recently that intramembrane proteolysis of the final membrane-bound N-terminal fragment (NTF) of CD74 is catalysed by Signal-peptide-peptidase-like 2a (SPPL2a) and that this process is indispensable for development and function of B lymphocytes in mice. In SPPL2a-/- mice, homeostasis of these cells is disturbed by the accumulation of the unprocessed CD74 NTF. So far, evidence for this essential role of SPPL2a is restricted to mice. Nevertheless, inhibition of SPPL2a has been suggested as novel approach to target B cells for treating autoimmunity. Here, we characterize human B cell lines with a homozygous microdeletion on chromosome 15. We demonstrate that this deletion disrupts the SPPL2a genomic locus and leads to loss of SPPL2a transcript. Lymphoblastoid cell lines from patients with this deletion exhibit absence of SPPL2a at the protein level and show an accumulation of the CD74 NTF comparable to B cells from SPPL2a-/- mice. By this means, we present evidence that the role of SPPL2a in CD74 proteolysis is conserved in human B cells and provide support for modulation of SPPL2a activity as a therapeutic concept.
Available from: Lucio Miele
- "This structure showed that the catalytic aspartates residues that reside within opposing transmembrane domains are in close proximity to each other and the lipid membrane surface. Some, but not all, GSIs inhibit signal peptide peptidases as well, though this has not been systemically studied[36,41]. When considering biological activities of various GSIs this is an important and understudied caveat that could influence both biological response as well as potential toxicities. Indeed, it has been reported that SPP, and not PSEN1 or PSEN2, is the major binding target of a GSI in some cells, which likely reflects the fact that in most cells SPP is much more abundant then PSEN/γ-secretase. "
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ABSTRACT: γ-Secretase is a fascinating, multi-subunit, intramembrane cleaving protease that is now being considered as a therapeutic target for a number of diseases. Potent, orally bioavailable γ-secretase inhibitors (GSIs) have been developed and tested in humans with Alzheimer's disease (AD) and cancer. Preclinical studies also suggest the therapeutic potential for GSIs in other disease conditions. However, due to inherent mechanism based-toxicity of non-selective inhibition of γ-secretase, clinical development of GSIs will require empirical testing with careful evaluation of benefit versus risk. In addition to GSIs, compounds referred to as γ-secretase modulators (GSMs) remain in development as AD therapeutics. GSMs do not inhibit γ-secretase, but modulate γ-secretase processivity and thereby shift the profile of the secreted amyloid β peptides (Aβ) peptides produced. Although GSMs are thought to have an inherently safe mechanism of action, their effects on substrates other than the amyloid β protein precursor (APP) have not been extensively investigated. Herein, we will review the current state of development of GSIs and GSMs and explore pertinent biological and pharmacological questions pertaining to the use of these agents for select indications. This article is part of a Special Issue entitled: Intramembrane Proteases.
Available from: Cristian R Smulski
- "It is also well documented that membrane-bound TNF or FasL are shed by cleavage with metalloproteases (TACE, ADAM10), leaving behind on the expressing cell the transmembrane segment and intracellular domain of the ligands. The transmembrane domain is thereafter processed by signal peptide peptidase-like aspartyl proteases that release in the producing cell the intracellular domains of TNF or FasL that can migrate and signal in the nucleus , , , . The mechanism by which atacicept promoted CNS inflammation in patients with relapsing-remitting multiple sclerosis remains unknown. "
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ABSTRACT: Myeloid cells express the TNF family ligands BAFF/BLyS and APRIL, which exert their effects on B cells at different stages of differentiation via the receptors BAFFR, TACI (Transmembrane Activator and CAML-Interactor) and/or BCMA (B Cell Maturation Antigen). BAFF and APRIL are proteins expressed at the cell membrane, with both extracellular and intracellular domains. Therefore, receptor/ligand engagement may also result in signals in ligand-expressing cells via so-called "reverse signalling". In order to understand how TACI-Fc (atacicept) technically may mediate immune stimulation instead of suppression, we investigated its potential to activate reverse signalling through BAFF and APRIL. BAFFR-Fc and TACI-Fc, but not Fn14-Fc, reproducibly stimulated the ERK and other signalling pathways in bone marrow-derived mouse macrophages. However, these effects were independent of BAFF or APRIL since the same activation profile was observed with BAFF- or APRIL-deficient cells. Instead, cell activation correlated with the presence of high molecular mass forms of BAFFR-Fc and TACI-Fc and was strongly impaired in macrophages deficient for Fc receptor gamma chain. Moreover, a TACI-Fc defective for Fc receptor binding elicited no detectable signal. Although these results do not formally rule out the existence of BAFF or APRIL reverse signalling (via pathways not tested in this study), they provide no evidence in support of reverse signalling and point to the importance of using appropriate specificity controls when working with Fc receptor-expressing myeloid cells.
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