Reactome | SPPL2a/b cleaves TNF(1-76)

SPPL2a/b cleaves TNF(1-76)

Stable Identifier

R-HSA-8863101

Type

Reaction [uncertain]

Species

Homo sapiens

Compartment

cytosol, extracellular region, plasma membrane

ReviewStatus

5/5

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The peptide fragment that remains after soluble TNFalpha is released by sheddases like ADAM17 is futher processed by intramembrane proteolysis, releasing an intracellular domain (ICD) into the cytoplasm and C-terminal fragments into the extracellular region (Fluhrer et al. 2006). SPP/SPPL proteins are intramembrane-cleaving aspartyl proteases. SPPL2a has been located in lysosomes/late endosomes of murine embryonic fibroblasts (Behnke et al. 2011) but when overexpressed in HeLa cells is found in significant amounts at the cell surface (Behnke et al. 2011). Overexpressed SPPL2b was detected primarily at the cell surface (Friedmann et al. 2006, Behnke et al. 2011). Overexpression or RNAi-mediated knockdown of either SPPL2a or SPPL2b in cell culture models demonstrates that both proteases are able to cleave TNFalpha (Fluhrer et al. 2006, Friedmann et al. 2006). SPPL2a/b-mediated intramembrane proteolysis of TNFalpha in bone marrow-derived dendritic cells was seen to up-regulate transcription and secretion of IL-12 (Friedmann et al. 2006). Whether TNFalpha ICD fragments can translocate to the nucleus and directly activates transcription of IL-12 gene is unknown. SPLL2a and b have a number of other substrates that suggest physiological roles within the hematopoietic system and for the regulation of inflammatory responses (Voss et al. 2013).

Literature References

PubMed ID	Title	Journal	Year
16829952	SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production Rovelli, G, Vreugde, S, Schleeger, S, Stauffer, D, Hauben, E, Friedmann, E, Martoglio, B, Lichtenthaler, SF, Kuhn, PH, Maylandt, K	Nat. Cell Biol.	2006
16829951	A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b Israel, L, Fluhrer, R, Haass, C, Haffner, C, Teplow, DB, Imhof, A, Friedmann, E, Martoglio, B, Böhland, C, Grammer, G, Condron, MM	Nat. Cell Biol.	2006