TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model

Yadav, Raj Kumar; Lee, Keum Hwa; Lee, Hwa Young; Li, Bo; Jung, Han Eul; Rashid, Harun Or; Choi, Min Kyung; Yadav, Binod Kumar; Kim, Woo Ho; Kim, Kyung Woon; Park, Byung Hyun; Kim, Won; Lee, Yong Chul; Kim, Hyung Ryong; Chae, Han-Jung

doi:10.1080/15548627.2015.1082021

Cited by 29 publications

(29 citation statements)

References 75 publications

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“…Nephrotoxic medications (cisplatin, cyclosporine) and heavy metals (arsenic, cadmium) mainly target the proximal tubules in the kidney and up-regulate autophagy in tissue culture experiments and murine models of toxic renal injury 25,113-121 . Autophagy is activated within the first hours of injury in models using cisplatin, cyclosporine, heavy metals or aristolochic acid measured by LC3-II accumulation and visualization of autophagosomes 119,122-124 .…”

Section: Introductionmentioning

confidence: 99%

“…Cyclosporine, a commonly used immunosuppressant, has similar effects on autophagy as cisplatin including causing ER stress, oxidative stress and tubular cell death. Autophagy is activated by cyclosporine-induced cellular stress and autophagy alleviates injury both in acute and chronic cyclosporine injury models 69,120,121,126 . Furthermore, cyclosporine induces hemodynamic changes in the kidney, possibly leading to ischemia, and also increases ROS production, apoptosis and ER stress in the tubules.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy and Tubular Cell Death in the Kidney

Havasi

Dong

2016

Seminars in Nephrology

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Summary Many common renal insults such as ischemia and toxic injury primarily target the tubular epithelial cells especially the highly metabolically active proximal tubular segment. Tubular epithelial cells are particularly dependent on autophagy to maintain homeostasis and respond to stressors. The pattern of autophagy in the kidney has a unique spatial and chronological signature. Recent evidence shows that there is a complex crosstalk between autophagy and various cell death pathways. The purpose of this review is to specifically discuss the interplay between autophagy and cell death in the renal tubular epithelia. It is imperative to review this topic because recent discoveries have improved our mechanistic understanding of the autophagic process and have highlighted its broad clinical applications, making autophagy a major target for drug development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy and Tubular Cell Death in the Kidney

Havasi

Dong

2016

Seminars in Nephrology

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“…Requires stimuli/ intervention to determine autophagic flux. [6][7][8][9][10][11][12][13][14]16,17 Immuno-histochemistry Suitable for studying protein expression changes within specific regions of the renal cortex.…”

Section: Methodsmentioning

confidence: 99%

“…11,12 The significance of autophagy and the role it plays in the development of renal pathology has risen to prominence in recent years, but few have addressed changes in autophagic flux in vivo. [6][7][8][9][10][11][12][13][14][15][16][17][18] Many investigations have attempted to address perturbations in autophagy activity without addressing the fundamental question of whether autophagic flux is altered under the pathological milieu that is being studied.…”

Section: Introductionmentioning

confidence: 99%

Methods in renal research: Measurement of autophagic flux in the renal cortex ex vivo

2018

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The role of autophagy in the kidney and many nephrological diseases has gained prominence in recent years. Much of this research has been focused on markers of autophagy that are static and reveal little about the state of this dynamic pathway. Other mechanistic investigations are limited to in vitro studies, that often provide circumstantial evidence of autophagic flux. Here we describe a method for measuring autophagic flux ex vivo that allows more direct observations to be made in situ regarding the state of autophagic flux within the renal cortex of a single animal.

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“…17 FAIM2 knockdown reduces proliferation and cell adhesion but enhances non-adherent growth and migration, thus contributing to a higher metastatic potential. 20 Accumulating lines of evidence suggest that TMBIM family proteins, in addition to regulating apoptotic cell death, function in diverse biological pathways including autophagy. FAIM2 is one of the six members of the TMBIM family (transmembrane BAX inhibitor motif containing), which share the UPF0005 domain, Bax inhibitor-1 (BI-1)-like properties, and anti-apoptotic function.…”

Section: Introductionmentioning

confidence: 99%

Fas‐apoptotic inhibitory molecule 2 localizes to the lysosome and facilitates autophagosome‐lysosome fusion through the LC3 interaction region motif–dependent interaction with LC3

et al. 2019

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Abbreviations: BafA1, bafilomycin A1; BI-1, bax inhibitor-1; CASP, caspase; ER, endoplasmic reticulum; FAIM2, Fas-apoptotic inhibitory molecule 2; GABARAP, GABA type A receptor-associated protein; IDPR, intrinsically disordered protein region; LIR, LC3-interacting region; MAP1LC3B, microtubuleassociated protein 1 light chain 3 beta; MTOR, mammalian target of rapamycin; shRNA, small hairpin RNA; STX17, syntaxin 17; TMBIM, transmembrane BAX inhibitor motif containing. AbstractFas-apoptotic inhibitory molecule 2 (FAIM2) is a member of the transmembrane BAX inhibitor motif-containing (TMBIM) family. TMBIM family is comprised of six anti-apoptotic proteins that suppress cell death by regulating endoplasmic reticulum Ca 2+ homeostasis. Recent studies have implicated two TMBIM proteins, GRINA and BAX Inhibitor-1, in mediating cytoprotection via autophagy. However, whether FAIM2 plays a role in autophagy has been unknown. Here we show that FAIM2 localizes to the lysosomes at basal state and facilitates autophagy through interaction with microtubule-associated protein 1 light chain 3 proteins in human neuroblastoma SH-SY5Y cells. FAIM2 overexpression increased autophagy flux, while autophagy flux was impaired in shRNA-mediated knockdown (shFAIM2) cells, and the impairment was more evident in the presence of rapamycin. In shFAIM2 cells, autophagosome maturation through fusion with lysosomes was impaired, leading to accumulation of autophagosomes. A functional LC3-interacting region motif within FAIM2 was essential for the interaction with LC3 and rescue of autophagy flux in shFAIM2 cells while LC3-binding property of FAIM2 was dispensable for the antiapoptotic function in response to Fas receptor-mediated apoptosis. Suppression of autophagosome maturation was also observed in a null mutant of Caenorhabditis elegans lacking xbx-6, the ortholog of FAIM2. Our study suggests that FAIM2 is a novel regulator of autophagy mediating autophagosome maturation through the interaction with LC3.

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TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model

Abstract: (2015) TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model,

Cited by 29 publications

References 75 publications

Autophagy and Tubular Cell Death in the Kidney

Autophagy and Tubular Cell Death in the Kidney

Methods in renal research: Measurement of autophagic flux in the renal cortex ex vivo

Fas‐apoptotic inhibitory molecule 2 localizes to the lysosome and facilitates autophagosome‐lysosome fusion through the LC3 interaction region motif–dependent interaction with LC3

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