Featured interactome of homocysteine-inducible endoplasmic reticulum protein uncovers novel binding partners in response to ER stress

Su, Rui; Yin, Jialing; Ruan, Xiaolan; Chen, Yanxi; Wan, Pin; Luo, Zhen

doi:10.1016/j.csbj.2023.09.006

Cited by 2 publications

(2 citation statements)

References 50 publications

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“…Hence, one can also anticipate that changes in AUP1 and OS9 abundance could also modify the expression of the cotransporters in vivo. In line with this hypothesis, previous studies have reported that AUP1 and OS9 are up-regulated in response to ER stress and facilitate the ERAD of glycoproteins in a cellular context of ER stress [57,58]. In this regard, the AUP1 and OS9 overexpression approach used in our study may mimic, therefore, AUP1 and OS9 upregulation under situations generating ER stress in renal cells, such as chronic high salt intake and aging [59,60].…”

Section: Discussionsupporting

confidence: 84%

AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination of NKCC2

Frachon,

Demaretz,

Seaayfan

et al. 2024

Cells

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Inactivating mutations of kidney Na-K-2Cl cotransporter NKCC2 lead to antenatal Bartter syndrome (BS) type 1, a life-threatening salt-losing tubulopathy. We previously reported that this serious inherited renal disease is linked to the endoplasmic reticulum-associated degradation (ERAD) pathway. The purpose of this work is to characterize further the ERAD machinery of NKCC2. Here, we report the identification of ancient ubiquitous protein 1 (AUP1) as a novel interactor of NKCC2 ER-resident form in renal cells. AUP1 is also an interactor of the ER lectin OS9, a key player in the ERAD of NKCC2. Similar to OS9, AUP1 co-expression decreased the amount of total NKCC2 protein by enhancing the ER retention and associated protein degradation of the cotransporter. Blocking the ERAD pathway with the proteasome inhibitor MG132 or the α-mannosidase inhibitor kifunensine fully abolished the AUP1 effect on NKCC2. Importantly, AUP1 knock-down or inhibition by overexpressing its dominant negative form strikingly decreased NKCC2 polyubiquitination and increased the protein level of the cotransporter. Interestingly, AUP1 co-expression produced a more profound impact on NKCC2 folding mutants. Moreover, AUP1 also interacted with the related kidney cotransporter NCC and downregulated its expression, strongly indicating that AUP1 is a common regulator of sodium-dependent chloride cotransporters. In conclusion, our data reveal the presence of an AUP1-mediated pathway enhancing the polyubiquitination and ERAD of NKCC2. The characterization and selective regulation of specific ERAD constituents of NKCC2 and its pathogenic mutants could open new avenues in the therapeutic strategies for type 1 BS treatment.

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Section: Discussionsupporting

confidence: 84%

AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination of NKCC2

Frachon,

Demaretz,

Seaayfan

et al. 2024

Cells

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“…Analogously, modulations of AUP1 or OS9 protein levels could also alter NKCC2 abundance and function in vivo. In this regard, both proteins are upregulated during ER stress and promote the ERAD of glycoproteins under these conditions [58,61]. Overexpression studies of AUP1 and OS9 may therefore mimic their upregulation under circumstances of ER stress in kidney cells, for example, in chronic high dietary salt intake and aging, during which NKCC2 is downregulated [62][63][64][65].…”

Section: Interaction With Os9 and Aup1mentioning

confidence: 99%

Protein Quality Control of NKCC2 in Bartter Syndrome and Blood Pressure Regulation

Laghmani

2024

Cells

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Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. Given the importance of NKCC2 in salt-sensitive hypertension and the pathophysiology of prenatal BS, studying the molecular regulation of this Na-K-2Cl cotransporter has attracted great interest. Therefore, several studies have addressed various aspects of NKCC2 regulation, such as phosphorylation and post-Golgi trafficking. However, the regulation of this cotransporter at the pre-Golgi level remained unknown for years. Similar to several transmembrane proteins, export from the ER appears to be the rate-limiting step in the cotransporter’s maturation and trafficking to the plasma membrane. The most compelling evidence comes from patients with type 5 BS, the most severe form of prenatal BS, in whom NKCC2 is not detectable in the apical membrane of thick ascending limb (TAL) cells due to ER retention and ER-associated degradation (ERAD) mechanisms. In addition, type 1 BS is one of the diseases linked to ERAD pathways. In recent years, several molecular determinants of NKCC2 export from the ER and protein quality control have been identified. The aim of this review is therefore to summarize recent data regarding the protein quality control of NKCC2 and to discuss their potential implications in BS and blood pressure regulation.

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Featured interactome of homocysteine-inducible endoplasmic reticulum protein uncovers novel binding partners in response to ER stress

Cited by 2 publications

References 50 publications

AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination of NKCC2

AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination of NKCC2

Protein Quality Control of NKCC2 in Bartter Syndrome and Blood Pressure Regulation

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