Disease relevance of Tpp2

• We demonstrate here that tripeptidyl peptidase II (TPPII), a cytoplasmic, high-molecular-weight protease, participates in the apoptotic pathway triggered by Shigella [1].
• These results suggest that the activities of both the proteasome and TPPII are regulated in a parallel manner in cancer cachexia, and that both are induced by the same factor and probably have the same intracellular signalling pathways and transcription factors [2].
• To investigate if a relationship exists between the activity of the proteasome and TPPII, functional activities have been measured in gastrocnemius muscle of mice bearing the MAC16 tumour, and with varying extents of weight loss [2].

High impact information on Tpp2

• We also find, in studies of apoptosis resistant cells derived from large in vivo tumors, that these have acquired an altered peptidase activity, with up-regulation of TPP II activity and decreased proteasomal activity [3].
• However, proteasomes in vivo (like purified proteasomes) release relatively few such peptides, and these peptides processed by TPPII require further trimming in the endoplasmic reticulum (ER) by ER aminopeptidase 1 for presentation [4].
• Tripeptidyl peptidase II is the major peptidase needed to trim long antigenic precursors, but is not required for most MHC class I antigen presentation [4].
• However, our results suggest that eubacterial PepN and its homologues displaying aminoendopeptidase activities may be "functionally similar" to enzymes important in downstream processing of proteins in the cytosol: Tricorn-F1-F2-F3 complex in Archaea and TPPII/Multicorn in eukaryotes [5].
• Both AAF-cmk and lactacystin prevented the maturation of pro-caspase-1 and its substrate pro-interleukin 1beta in Shigella-infected macrophages, indicating that TPPII is upstream of caspase-1 [1].

Biological context of Tpp2

• Characterization of cDNA for murine tripeptidyl-peptidase II reveals alternative splicing [6].
• The deduced amino acid sequence shows a 96% overall identity when compared with the previously cloned human TPP II [6].
• Tripeptidyl-peptidase II (TPP II) is a cytosolic high-M(r) exopeptidase with an active site of the subtilisin type [6].
• The gene encoding tripeptidyl peptidase II maps to chromosome 1 in the mouse [7].
• The insert within the catalytic domain of tripeptidyl-peptidase II is important for the formation of the active complex [8].

Anatomical context of Tpp2

• This was surprising because native human TPP II is purified from erythrocytes as an active oligomeric complex, and the amino-acid sequences of the human and murine enzymes were 96% identical [8].
• Effect of cancer cachexia on the activity of tripeptidyl-peptidase II in skeletal muscle [2].
• In murine myotubes, proteolysis-inducing factor, which is a sulphated glycoprotein produced by cachexia-inducing tumours, induced an increase in activity of both proteasome and TPPII, with an identical dose-response curve, and both activities were inhibited by eicosapentaenoic acid [2].

Associations of Tpp2 with chemical compounds

• The TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) and clasto-lactacystin beta-lactone (lactacystin), an inhibitor of both TPPII and the proteasome, protected macrophages from Shigella-induced apoptosis [1].
• Administration of the lowest sublethal dosage of TOCP (0.25g/1Kg, 24 hours) resulted in significant inhibition (10 to 30% of control activity) of the cytoplasmic proteases tripeptidyl aminopeptidase and proline endopeptidase only [9].

Other interactions of Tpp2

• Consequently, higher concentrations of butabindide are required for the inhibition of CCK-8S degradation by TPP-I than by TPP-II [10].
• An increasing dosage of TOCP (1g/Kg for 7 days) resulted in significant inhibition (10 to 50% of control activity) of the cytoplasmic proteases alanyl aminopeptidase, leucyl aminopeptidase, tripeptidyl aminopeptidase, and proline endopeptidase, as well as the lysosomal proteases dipeptidyl aminopeptidase I and cathepsins B, D, and L [9].

References