TMP21 degradation is mediated by the ubiquitin‐proteasome pathway

Abstract

The presenilin-associated complex regulates two independent intramembranous cleavage activities, i.e. gamma-secretase and epsilon-secretase activity. The gamma-secretase complex requires four critical components for its activity: presenilin 1, anterior pharynx-defective 1, nicastrin 1 and presenilin enhancer 2, all of which are degraded through the ubiquitin-proteasome pathway. Recently, TMP21, a type I transmembrane protein involved in endoplasmic reticulum/Golgi transport, was identified as a member of the presenilin complex. Knockdown of TMP21 selectively regulated pathogenic gamma-secretase activity, resulting in increased amyloid beta protein 40 and 42, without affecting the epsilon-cleavage of Notch. A further understanding of TMP21 degradation is required to examine the biological consequences of TMP21 protein level aberrations and their potential role in the pathogenesis of Alzheimer's disease and drug development. Here we show that human TMP21 has a short half-life of approximately 3 h. Treatment with proteasomal inhibitors can increase TMP21 protein levels in both a time- and dose-dependent manner, and both co-immunoprecipitation and immunofluorescent staining show that TMP21 is ubiquitinated. Inhibition of the lysosomal pathway failed to show a dose-dependent increase in TMP21 protein levels. Taken together, these results indicate that the degradation of TMP21, as with the other presenilin-associated gamma-secretase complex members, is mediated by the ubiquitin-proteasome pathway.

Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone‐mediated autophagy and ubiquitin proteasome pathways

“…Ubiquitin deposition has been observed in neurofibrillary tangles of AD, Lewy bodies of Parkinson's disease, and Bunina bodies of amyotrophic lateral sclerosis (ALS), as well as nuclear inclusions in Huntington's disease, spinocerebellar ataxias, and Kennedy's disease (46). Many proteins involved in AD pathogenesis, including tau (47,48), the APP C terminus (49 -51), BACE1 (31), PS1 (52-54), PS2 (55), Nct-1 (56), Pen-2 (57, 58), Aph-1 (59,60), and TMP21 (61), are degraded by ubiquitin-proteasome pathways. Our work and other studies have demonstrated that RCAN1 can be ubiquitinated and that inhibition of proteasome markedly increases RCAN1 levels (29,62,63).…”

The proteasomal system

“…Until now about 160 of such mutations are known, causing a positive shift of the ratio Ab 42 :Ab 40 , that induces accumulation of Ab and thus the pathology of AD. Even if the four mentioned proteins are required and sufficient for c-secretase functionality, further proteins have been found, that might fulfill a regulator function and seem to be constitutive parts of the c-secretase complex: CD147 , TMP21 (Liu et al, 2008; and Rer1p (Spasic et al, 2007). Removal of CD147 from c-secretase results in an increased formation of Ab-peptides, while overexpression leads to a quick degradation of Ab.…”

“…It might be possible that the decreased degradation of Ab is in part due to the known age-dependent reduced proteasomal activity Breusing and Grune, 2008). But not only Ab is proteasomal degraded: PS1 and PS2 (Marambaud et al, 1998;Kim et al, 1997), as well as other proteins found in the c-secretase complex like nicastrin , Aph-1 , Pen-2 (Bergman et al, 2004) and TMP21 (Liu et al, 2008) are all proteasomal degraded or their cellular amounts are regulated by the UPS.…”

Putative p24 complexes in Arabidopsis contain members of the delta and beta subfamilies and cycle in the early secretory pathway

“…To the authors’ knowledge, there is only one previous study dealing with the mechanism of degradation of p24 proteins. In particular, TMP21 (also named p23, p24δ subfamily), a member of the presenilin complex, has been shown to have a short half-life of ~3h and to be degraded by the ubiquitin–proteasome pathway: while treatment with the proteasomal inhibitor MG-132 caused a significant increase in TMP21 protein levels, lysosomal inhibition was without effect (Liu et al ., 2008). To the authors’ knowledge, there are no reports dealing with the degradation of p24 proteins of the beta subfamily.…”