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  • br Presenilins in protein trafficking proteolysis and degrad

    2022-01-27


    Presenilins in protein trafficking, proteolysis and degradation An obvious explanation for the role of presenilins and γ-secretase in protein trafficking and degradation is that many reported γ-secretase substrates are functionally involved in protein transport. For example, members of the mammalian Vsp10p sorting receptor family including sortilin-related receptor with A-type repeat SorLA (also known as SORL1, LR11), Sortilin and SorCS1b are reported to be γ-substrates [74], [75]. However, data from several other groups support the proposal that the presenilins can also affect trafficking independent of γ-secretase proteolysis activity. It has been shown that PS1 interacts with Rab11 [76], a small GTPase involved in the regulation of vesicular transport and several other Rab proteins have been reported to be involved in PS1-mediated protein trafficking, such as Rab6 and Rab GDP dissociation inhibitor [77], [78]. Consistent with this the presenilins have also been shown to regulate the trafficking and turnover of a number of proteins. For example, presenilin-deficient neurons have been shown to have reduced trafficking of TrkB and EphB receptors to the plasma membrane and diminished neuroprotective qualities of the EphB ligand, efnB [79], [80]. Interestingly, this efnB-associated neuroprotection is maintained in Nystatin treated with γ-secretase inhibitors, suggesting a γ-secretase independent function of the presenilins [80]. By contrast PS knockout cells showed an increase in integrin β1 trafficking to the cell surface and an increase in integrin β1 post-translational modification and maturation [81]. These results indicate that the presenilins play a role in chaperoning proteins through the endoplasmic reticulum (ER) to the Golgi independent of presenilins γ-secretase function. PS1 has also been shown to mediate epidermal growth factor receptor (EGFR) turnover via the endosomal/lysosomal system and as such regulates EGFR signalling [70]. Abnormal EGFR signalling in PS-deficient cells involves γ-secretase independent transcriptional down regulation of the E3 ligase Fbw7 and by affecting a proteasome-dependent ubiquitination step essential for constitutive degradation and stability of EGFR [38]. Additionally, a more recent study has reported that PS1 is necessary for cell-specific transcriptional regulation of EGFR expression and neuroprotection, in a γ-secretase independent manner [82]. The neuronal cell adhesion protein telencephalin also interacts with PS1 and has been shown to increase in half-life and accumulate in autophagic vacuoles in PS-deficient neurons [83]. Telencephalin trafficking was rescued by expression of wild type or catalytically inactive PS1 aspartate mutant and was not affected by γ-secretase inhibitors, demonstrating that this is a γ-secretase independent function of presenilins. Additionally, presenilins have been shown to regulate axonal transport via interactions with GSK-3β thus influencing kinesin-1 and dynein activity and role in transport [84], an activity that was insensitive to γ-secretase inhibitors [85]. Consistent with this, cells expressing PS1 FAD mutations and presenilin conditional knockout (PScDKO) mice show reduced kinesin-1 activity and reduced fast axonal transport (FAT) of type 1 transmembrane receptors [86], [87]. Filamin is a protein that is involved in regulating neuronal migration, and overexpression of the PS1 FAD M146L mutant alters filamin distribution within the cell from the cell periphery to the cytoplasm; this alteration is not changed by treatment with a γ-secretase inhibitor [88], suggesting that PS1 regulates filamin localization in a γ-secretase independent manner [89]. Collectively, these observations suggest that the presenilins play an important role in maintaining axonal transport within neurons and in regulating neuronal migration. PS1 deletion or PS1 FAD mutations have also been shown to disrupt lysosomal acidification and proteolysis, which inhibits autophagy (Fig. 3), a lysosomal degradative pathway for recycling damaged or obsolete organelles and misfolded or aggregated proteins [31], [32], [83], [90], [91], [92]. This function is again independent of presenilins' role as the catalytic subunit of γ-secretase [6], [31], [93]. It has been proposed that PS1 holoprotein serves as a chaperone in the ER for the vATPase V0a1 subunit, a transmembrane component of the proton pump responsible for the acidification of lysosomes [31]. Binding of PS1 in the ER is proposed to stabilize vATPase V0a1 and facilitate its glycosylation, a prerequisite for ER exit [31], [94], [95]. Oligosaccharyltransferase (OST), a multimeric complex located at the membrane of the ER, transfers a preassembled oligosaccharide to selected asparagine residues within the consensus sequence asparagine-X-serine/threonine. In PS1-deficient cells the vATPase V01a subunit is poorly glycosylated and unstable, which prevents proper assembly and function of the multisubunit vATPase pump, resulting in reduced acidification of lysosomes and defective autophagy [31], [33]. Consistent with this proposal several lysosome acidification defects and disrupted autophagy have been associates with loss of presenilin or FAD mutations [33], [95]. Interestingly, pharmacological inhibition of vATPase induces AD-related autophagy dysfunction and pathologies, while pharmacological normalization of lysosomal acidification in PS1-deficient cells reverses PS1-related defects [96]. In contrast to these studies, others have proposed an alternative model for presenilin function in autophagy, whereby it is proposed that N-glycosylation may not be necessary for the proper trafficking and function of vATPase V0a1 subunit but rather defective glycosylation of the vATPase V0a1 subunit and lysosomal acidification may arise due to disruption in lysosomal calcium storage and release [30]. However, a recent study has demonstrated that disruption in lysosomal calcium storage and release is secondary to dysfunctional lysosomal acidification in PS1-deficient cells [97]. It was demonstrated that abnormal calcium efflux from lysosomes in PS1-deficient cells are caused by a pH-sensitive activation of the endolysosomal calcium channel, transient receptor potential (TRP) cation channel mucoplin subfamily member 1 (TRPML1), which causes elevated cytosolic calcium. Collectively, these data indicate that PS1 deletion or PS1 FAD mutations cause lysosomal and autophagy deficits that contribute to abnormal cellular calcium homeostasis, thereby linking two AD-related pathogenic processes through a single molecular mechanism.