蛋白酶體功能障礙和蛋白質品質控制機制，例如內質網相關降解系統（ER-associated degradation, ERAD）在神經退化性蛋白囤積症，例如阿茲海默症（Alzheimer’s disease, AD）中普遍失調。特別是，AD患者腦組織中蛋白酶體活性以及關鍵的內質網相關降解系統組成蛋白，如膜蛋白membralin、E3泛素連接酶HRD1和AMFR，均有功能缺陷的現象。類澱粉前驅蛋白（amyloid precursor protein, APP）可經由連續的蛋白酶水解反應後生成β-類澱粉蛋白（amyloid-beta, Aβ），而負責水解APP蛋白酶中，β-分泌酶BACE1和γ-分泌酶的組成分子之一nicastrin，已被確認為ERAD降解系統的受質。泛素特異性胜肽酶19（ubiquitin-specific peptidase 19, USP19）是去泛素化酶（deubiquitinase, DUB）家族的成員，而先前研究已發現，USP19可能會抑制未折疊蛋白反應（unfolded protein response, UPR）而減少ERAD受質被降解。而主要分布於內質網的一種USP19特異型已被發現與帕金森氏症（Parkinson’s disease, PD）和AD等多種神經退化性疾病的致病機轉有密切關聯，因為它能夠促進錯誤折疊的細胞質蛋白藉由非常規的分泌路徑排出細胞外。哺乳動物細胞還會表現另一種主要分布於細胞質的USP19特異型，而USP19的內質網特異型和細胞質特異型已知各有不同的反應受質蛋白，根據轉錄體學資料分析顯示，哺乳動物細胞中USP19細胞質特異型是主要的表現型，代表其可能在哺乳動物以及人類的生理及病理反應中扮演重要的角色。本研究旨在闡明USP19如何經由哪些分子機制調控ERAD、APP代謝、和Aβ胜肽生成反應。我們首先分析哺乳動物細胞中內源性USP19蛋白各個特異型的表現量，結果證實USP19細胞質特異型的全長型和C端片段（C-terminal fragment, CTF）是哺乳動物細胞中主要表現的USP19蛋白特異型。當我們利用過量表現APP的細胞（AY），再同時過量表現USP19內質網特異型（特異型4；USP19-ER）後，並未顯著影響APP全長型蛋白的恆定量；可是當AY細胞同時過量表現USP19細胞質特異型（特異型2；USP19-Cyto）時，則會導致APP全長型蛋白恆定量顯著增加，這時蛋白酶水解產生的APP蛋白片段總量也會同步增加。我們進一步發現，USP19-Cyto的CTF就足以維持USP19-Cyto全長型蛋白在調節APP蛋白恆定量的功效，兩者均具有DUB活性。在過量表現USP19-Cyto或其CTF的細胞中，APP泛素化程度的確會顯著降低。若是將USP19催化反應中心的三個核心胺基酸（Cys609/His1260/Asp1292）同時都以serine胺基酸取代時，則可完全剔除USP19的DUB酵素活性。我們接著利用共免疫沉澱法搭配細胞組成分離技術，發現USP19細胞質特異型主要會與細胞質中的APP全長型蛋白及伴護蛋白BAG6形成複合物，而存在於細胞質中的APP全長型蛋白多是一些去醣基化而被逆向轉運至細胞質中的APP蛋白。綜合以上所述，我們的研究結果揭示了USP19細胞質特異型在調控被APP泛素化和被蛋白酶體降解的全新功效，並將有助於我們理解當膜蛋白品質控制機轉異常時，會如何影響AD的致病機轉及病程演進。

Proteasomal dysfunction and protein quality control mechanisms such as the ER-associated degradation (ERAD) system is commonly dysregulated in neurodegenerative proteinopathies, such as Alzheimer's disease (AD). In particular, proteasome activity along with key ERAD components membralin, E3 ubiquitin ligases HRD1 and AMFR, were found to be deficient in AD brains. Amyloid precursor protein (APP) which can undergo sequential amyloidogenic processing to produce amyloid-beta (Aβ), and other components of APP processing, such as β-secretase BACE1 and γ-secretase subunit nicastrin, have been identified as ERAD substrates. Ubiquitin-specific peptidase 19 (USP19), a member of the deubiquitinase (DUB) family, was discovered to function in the unfolded protein response (UPR) by rescuing ERAD substrates. Recently, an ER-localized isoform of USP19 has been implicated in several neurodegenerative diseases, such as PD and AD, due to its function in facilitating the unconventional secretion of misfolded cytosolic proteins. While the ER-localized and cytosolic isoforms of USP19 are found to target different substrates, a transcriptomic dataset indicates cytosolic isoforms of USP19 as the predominantly expressed variants, suggesting their potential roles in disease conditions. This study aims to clarify the roles of USP19 in the regulation of ERAD, APP metabolism, and amyloid-beta (Aβ) peptide production. We first characterized the endogenous USP19 within mammalian cell lines, validating that full-length and cleaved C-terminal fragment (CTF) of cytosolic USP19 are the most abundant species. While overexpression of ER-localized USP19 (Isoform 4; USP19-ER) in APP-expressing cells (AY) did not cause any significant change to the level of full-length APP, overexpression of the major cytosolic USP19 isoform (Isoform 2; USP19-Cyto) resulted in significant increases in the levels of full-length APP and its proteolytic fragments. Our data also demonstrated that USP19-Cyto CTF is able to recapitulate the effect of full-length USP19-Cyto on APP proteostasis, with both species being DUB active. Cells overexpressing either USP19-Cyto or its CTF exhibited a significant reduction in APP ubiquitination, with the effect fully ablated when all three residues within the catalytic triad (Cys609/His1260/Asp1292) of USP19 are simultaneously replaced. Using co-immunoprecipitation in combination with subcellular fractionation, we revealed that cytosolic USP19 preferentially interacts with a deglycosylated, retrotranslocated form of APP in complex with the chaperone BAG6 within the cytosolic fraction. Collectively, our current findings demonstrate the novel role of cytosolic USP19 in regulating the ubiquitination and proteasomal degradation of APP, and could contribute to the understanding of how aberrations in membrane protein quality control could impact AD pathogenesis.

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