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  • It has also been demonstrated that

    2022-01-21

    It has also been demonstrated that PS1 is ubiquitinated by Caenorhabditis elegans SEL-10 [52], Fbw7 the mammalian homologue of SEL-10 [38], and more recently by tumour necrosis factor Decanoyl-RVKR-CMK associated factor 6 (TRAF6), which facilitates Lysine-63 (K63)-linked polyubiquitination of PS1 [50], [51]. The ubiquitination of PS1 by C. elegans SEL-10 targets PS1 for degradation through the ubiquitin–proteasome system and antagonizes the signalling activity of Notch [52]. Consistent with this, PS1 and Fbw7 interact and regulate the stability and activity of the epidermal growth factor receptor (EGFR) and the Notch ICD (NICD) [38]. The presenilins contain a conserved TRAF6-binding domain [59], [60] and undergo TRAF6-mediated K63-linked polyubiquitination, [50], [51] which increases PS1 holoprotein stability and function in the regulation of calcium homeostasis, independent of γ-secretase protease activity [50]. Furthermore, the interaction between TRAF6 and PS1 has been shown to promote γ-secretase cleavage of p75 neurotrophin receptor (p75NTR) [60], while the loss of TRAF6 E3 ligase activity reduces γ-secretase cleavage of p75NTR, TGFβ Type 1 Receptor (TβR1) and interleukin-1 receptor, type 1 (IL-1R1) [51], [61]. These data suggests that the interaction between TRAF6, PS1 and γ-secretase substrates plays a role in modulating γ-secretase activity. However, given that TRAF6 can ubiquitinate both PS1 and some γ-secretase substrates, the exact role-played by TRAF6 mediated ubiquitination of PS1 remains to be fully elucidated. What is clear is that these modifications are not Decanoyl-RVKR-CMK only important for the protease assembly and activity of γ-secretase complexes, but are also essential for the stability and activation of presenilins. The recognition of ubiquitin and polyubiquitin chains by ubiquitin-binding domains (UBDs) is critical for determining the outcome of ubiquitination and subsequent ubiquitin-mediated signalling pathways [62]. To date approximately 20 different UBDs have been identified, including ubiquitin interacting motifs (UIMs), ubiquitin associated domains (UBAs) and the related coupling of ubiquitin conjugation to endoplasmic reticulum degradation (CUE) domains [63]. In keeping with a role for ubiquitination in the regulation of presenilin activities, the UBA of ubiquilin is necessary for the binding of ubiquilin to PS1 and PS2 [64], which reduces the formation of NTF/CTF heterodimers by stabilizing presenilin holoproteins within the cell [65]. Ubiquilin transcript variants (TV) 1 and 3 have been shown to cause the accumulation of higher molecular weight forms of PS1 (HMW-PS1) [66]. Ubiquilin is hypothesised to act as a shuttle between ubiquitinated proteins and the proteasome and it has been suggested that the accumulation of HMW-PS1 is a result of weak interactions between Ubiquilin-1 TV3 and the proteasome [66]. PS1 has recently been shown to contain a functional ubiquitin-binding CUE domain (Fig. 2C), which preferentially binds to K63-linked polyubiquitin chains [67]. Interestingly, missense CUE mutants that prevented binding to ubiquitin, do not affect endoproteolysis of PS1, signifying that formation of PS1NTF/CTF heterodimers does not require an intact CUE domain, but suggesting that the presence of the CUE domain may be important for a γ-secretase-independent PS1 holoprotein function. Furthermore, mutation of the CUE domain does not alter PS1-dependent γ-secretase cleave of APP or Notch, nor generation of Aβ40/42 peptides, advocating that the PS1 CUE domain is not necessary for γ-secretase activity [67]. Taken together, these results highlight a function for non-covalent ubiquitin signalling in the regulation of the presenilins and their role in both the γ-secretase-dependent and -independent functions. Further studies will no doubt define the precise regulatory role of post-translational modification in presenilin biology and functions, independent of and dependent upon its role as the catalytic subunit of γ-secretase.