TMEM74, a lysosome and autophagosome protein, regulates autophagy

Yu, Chuanfei; Wang, Lan; Lv, Bingfeng; Yang, Lu; Zeng, Ling’e; Chen, Yingyu; Ma, Dalong; Shi, Taiping; Wang, Lu

doi:10.1016/j.bbrc.2008.02.055

Cited by 50 publications

(38 citation statements)

References 20 publications

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“…TMEM74 modulates the formation of autophagolysosomes and subsequently accelerates functional autophagy (33). The results of the present study suggested that TMEM74 was a key gene involved in the atorvastatin-induced autophagy process, due to its overexpression following atorvastatin treatment.…”

Section: Discussionmentioning

confidence: 51%

Atorvastatin induces autophagic cell death in prostate cancer cells in vitro

Yuan

Peng

et al. 2015

Molecular Medicine Reports

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Abstract. Athough it is well known that apoptosis contributes to cancer cell death, the role of autophagy in cancer cell death has remained in dispute. Atorvastatin has been suggested to exhibit anti-cancer effects. The present study aimed to examine atorvastatin-induced autophagy-associated cell death and the autophagy-associated gene expression profile in the PC3 prostate carcinoma cell line. The atorvastatin-induced process of autophagy in PC3 cells was determined via evaluation of the cellular expression levels of autophagosomal marker light-chain-3 (LC3)-II, using immunoblotting and counting of green fluorescent protein (GFP)-LC3-transfected autophagic cells. Apoptosis was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and an MTT assay was used to evaluate cell viability. Total RNA of PC3 cells was isolated for characterization of the gene expression profile following atorvastatin treatment. Atorvastatin treatment of PC3 cells for 24 h increased the expression of green fluorescent protein-LC3-II by >25%, and expression continued for >72 h, while apoptosis was not significantly induced within this time period. Four genes associated with the autophagy machinery were also significantly upregulated. In the presence of atorvastatin, autophagy may be unable to abrogate cell damage and may therefore contribute to cellular dysfunction, leading to autophagic/type II programmed cell death. In response to atorvastatin treatment, the expression of genes involved in autophagic mediating pathways may have a role in tumor suppression. IntroductionProstate cancer is the most frequently diagnosed non-cutaneous malignancy and the second leading cause of death due to cancer amongst males worldwide (1). Treatment options for localized disease include watchful waiting, surgery and radiotherapy (2). However, in terms of a definitive treatment, despite developments in systemic chemotherapy strategies, minimal improvements in the quality of life and overall survival have been achieved amongst patients with prostate cancer (3). The development of novel treatment strategies for patients with advanced metastatic prostate cancers remains a challenge.The PC3 human prostate cancer cell line [p53-and phosphatase and tensin homolog (PTEN)-] was established from a prostatic adenocarcinoma, which was metastatic to bone. It has been extensively used as a cell model for the study of prostate cancer and is generally assumed to model an advanced stage of prostate cancer (4). PC3 cells are resistant to numerous chemotherapy drugs and apoptosis inducers (5,6).At o r va s t a t i n, a 3 -hyd r ox y-3 -m e t hylg lu t a r yl (HMG)-coenzyme A reductase inhibitor, is among the widely prescribed drugs used to lower cholesterol and prevent cardiovascular diseases (7). In addition to its cholesterol-lowering effect, atorvastatin has pro-apoptotic and anti-metastatic effects on prostate cancer cells (8,9). Parikh et al (10) hypothesized that atorvastatin may induce autophagy-associated cell death in PC3 cells. However, the...

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Section: Discussionmentioning

confidence: 51%

Atorvastatin induces autophagic cell death in prostate cancer cells in vitro

Yuan

Peng

et al. 2015

Molecular Medicine Reports

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“…Another targeted autophagy-associated protein, TMEM74 is exclusively connected to the autophagy network, since we found it interacts with BNIP3. BNIP3 and TMEM74 are involved in stress-induced autophagy regulation [37], [38]. Interestingly we found that BNIP3 is able to interact with a large number of proteins within the autophagy network acting at different steps of the autophagic process.…”

Section: Discussionmentioning

confidence: 74%

IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network

et al. 2011

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Autophagy is a conserved degradative pathway used as a host defense mechanism against intracellular pathogens. However, several viruses can evade or subvert autophagy to insure their own replication. Nevertheless, the molecular details of viral interaction with autophagy remain largely unknown. We have determined the ability of 83 proteins of several families of RNA viruses (Paramyxoviridae, Flaviviridae, Orthomyxoviridae, Retroviridae and Togaviridae), to interact with 44 human autophagy-associated proteins using yeast two-hybrid and bioinformatic analysis. We found that the autophagy network is highly targeted by RNA viruses. Although central to autophagy, targeted proteins have also a high number of connections with proteins of other cellular functions. Interestingly, immunity-associated GTPase family M (IRGM), the most targeted protein, was found to interact with the autophagy-associated proteins ATG5, ATG10, MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles virus (MeV), Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1)-induced autophagy and viral particle production. Moreover we found that the expression of IRGM-interacting MeV-C, HCV-NS3 or HIV-NEF proteins per se is sufficient to induce autophagy, through an IRGM dependent pathway. Our work reveals an unexpected role of IRGM in virus-induced autophagy and suggests that several different families of RNA viruses may use common strategies to manipulate autophagy to improve viral infectivity.

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“…Available reports of this protein are limited and indicate that it functions as an autophagy inducer. 29,30 Further study may reveal alternative activities for Tmem74, which may explain the apparent inconsistency we observed between its expression and Dram1 in our mouse models and human patients.…”

Section: Discussionmentioning

confidence: 78%

L450W and Q455KCol8a2Knock-In Mouse Models of Fuchs Endothelial Corneal Dystrophy Show Distinct Phenotypes and Evidence for Altered Autophagy

Meng

Matthaei

Ramanan

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We compared the cellular phenotypes and studied the role of autophagy in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD) using two a2 collagen VIII (Col8a2) knock-in mouse models and human FECD tissues. METHODS.In vivo corneal endothelial cell (CEC) counts and morphology were analyzed by clinical confocal microscopy. Ultrastructural analysis of CECs was performed by transmission electron microscopy. Real-time PCR and Western blotting were performed using total RNA, and protein extracted from mouse CECs and human CECs obtained from FECD and autopsy patients.RESULTS. Both Col8a2 mouse models exhibited hallmarks of FECD; however, the Col8a2 L450W/L450W mice exhibited a milder phenotype compared to the Col8a2 Q455K/Q455K mice. Both models exhibited upregulation of the unfolded protein response (UPR) as evidenced by dilated rough endoplasmic reticulum (RER), and upregulation of UPR-associated genes and proteins. Real-time PCR of Col8a2 L450W/L450W and Col8a2 Q455K/Q455K CECs at 40 weeks revealed a 2.1-fold (P < 0.05) and a 5.2-fold (P < 0.01) upregulation of the autophagy marker Dram1, respectively. Real-time PCR of human FECD endothelium revealed a 10.4-fold upregulation of DRAM1 (P < 0.0001) compared to autopsy controls. CONCLUSIONS. The Col8a2L450W/L450W and Col8a2

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TMEM74, a lysosome and autophagosome protein, regulates autophagy

Cited by 50 publications

References 20 publications

Atorvastatin induces autophagic cell death in prostate cancer cells in vitro

Atorvastatin induces autophagic cell death in prostate cancer cells in vitro

IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network

L450W and Q455KCol8a2Knock-In Mouse Models of Fuchs Endothelial Corneal Dystrophy Show Distinct Phenotypes and Evidence for Altered Autophagy

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