Microtubule-associated Protein 1 Light Chain 3 (LC3) Interacts with Bnip3 Protein to Selectively Remove Endoplasmic Reticulum and Mitochondria via Autophagy

Hanna, Rita; Quinsay, Melissa N.; Orogo, Amabel M.; Giang, Kayla; Rikka, Shivaji; Gustafsson, Åsa B.

doi:10.1074/jbc.m111.322933

Cited by 607 publications

(481 citation statements)

References 45 publications

(58 reference statements)

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“…In yeast, selective autophagic clearance of mitochondria, mitophagy, requires an interaction between Atg11 and the protein Atg32, a receptor protein anchored to the outer mitochondrial membrane (33). The mammalian counterparts of Atg32 are the integral membrane receptors BNIP3 (BCL2/adenovirus E1B 19 kd-interacting protein 3) and BNIP3L/NIX (34,35). Immunoprecipitation of MYC-tagged BNIP3 or BNIP3L/NIX after cotranfection with Venus-tagged HTT(2416-3144) followed by Western blotting (Fig.…”

Section: Resultsmentioning

confidence: 99%

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Ochaba

Lukácsovich²,

Csikos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

254

228

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Although dominant gain-of-function triplet repeat expansions in the Huntingtin (HTT) gene are the underlying cause of Huntington disease (HD), understanding the normal functions of nonmutant HTT protein has remained a challenge. We report here findings that suggest that HTT plays a significant role in selective autophagy. Loss of HTT function in Drosophila disrupts starvationinduced autophagy in larvae and conditional knockout of HTT in the mouse CNS causes characteristic cellular hallmarks of disrupted autophagy, including an accumulation of striatal p62/SQSTM1 over time. We observe that specific domains of HTT have structural similarities to yeast Atg proteins that function in selective autophagy, and in particular that the C-terminal domain of HTT shares structural similarity to yeast Atg11, an autophagic scaffold protein. To explore possible functional similarity between HTT and Atg11, we investigated whether the C-terminal domain of HTT interacts with mammalian counterparts of yeast Atg11-interacting proteins. Strikingly, this domain of HTT coimmunoprecipitates with several key Atg11 interactors, including the Atg1/Unc-51-like autophagy activating kinase 1 kinase complex, autophagic receptor proteins, and mammalian Atg8 homologs. Mutation of a phylogenetically conserved WXXL domain in a C-terminal HTT fragment reduces coprecipitation with mammalian Atg8 homolog GABARAPL1, suggesting a direct interaction. Collectively, these data support a possible central role for HTT as an Atg11-like scaffold protein. These findings have relevance to both mechanisms of disease pathogenesis and to therapeutic intervention strategies that reduce levels of both mutant and normal HTT.rodegenerative disorder caused by an expansion of a CAG trinucleotide repeat encoding a polyglutamine (polyQ) tract near the N terminus of the 350-kD Huntingtin protein (HTT) (1). Identifying the normal biological function of the HTT protein is important in the effort to design and implement effective therapeutic interventions for HD, but has proved challenging.In the mouse, loss of HTT leads to lethality during gastrulation at embryonic day 7 (2-4). Conditional inactivation of HTT in the mouse forebrain at postnatal or late embryonic stages causes a progressive neurodegenerative phenotype associated with neuronal degeneration, motor phenotypes, and early mortality (5). Loss of HTT in mouse cells reduces primary cilia formation, and deletion of HTT in ependymal cells leads to alteration of the cilia layer, suggesting a role for HTT in ciliogenesis (6). Mutant HTT expression and HTT knockdown have also been found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7-9). A clear molecular mechanism to relate these findings to the function of the HTT protein, however, has not yet emerged.In contrast to the embryonic lethality observed in the mouse, Drosophila lacking the endogenous Htt gene develop normally. However, adult Drosophila HTT loss-of-function (LOF) flies show an accelerated neurodege...

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Section: Resultsmentioning

confidence: 99%

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Ochaba

Lukácsovich²,

Csikos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

254

228

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“…Furthermore, several lines of evidence demonstrate the participation of other receptors during autophagosomal recognition of mitochondria, including BNIP3L, BNIP3, and FUNDC1, hence the potential involvement of those receptors in mitophagy regulation of cigarette-induced cellular senescence need to be examined in future studies. [18][19][20][21] Programmed cell death (PCD) has been widely implicated in COPD pathogenesis and the involvement of autophagy, including mitophagy, has been reported in not only apoptosis but also programmed necrosis, necroptosis. 32,33 The central purpose of both PCD and cell senescence is eliminating damaged cells for tissue regeneration, indicating that the extent of cell damage may be critical for determination of cell fate.…”

Section: Wwwtandfonlinecommentioning

confidence: 99%

“…16 Proteins localized on the mitochondrial outer membrane, including BNIP3L, BNIP3, and FUNDC1 (FUN14 domain containing 1), are specific receptors for mitophagic recognition during red blood cell maturation, metabolic stress, and hypoxia. [18][19][20][21] Thus far, the PINK1-PARK2 pathway has been largely implicated in the removal of damaged mitochondria with depolarized membranes. 22 Stress-induced membrane depolarization stabilizes PINK1, resulting in recruitment of PARK2, an E3-ubiquitin ligase, to mitochondria.…”

Section: Introductionmentioning

confidence: 99%

PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis

et al. 2015

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(2015) PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis , Autophagy, 11:3, 547-559, DOI: 10.1080/15548627.2015 Abbreviations: Baf A1, bafilomycin A 1 ; COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; CSE, cigarette smoke extract; EM, electron microscopy; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; HBEC, human bronchial epithelial cell; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; NAC, N-acetylcysteine; PCD, programmed cell death; PINK1, PTEN-induced putative kinase 1; ROS, reactive oxygen species; SA-b-Gal, senescence-associated b-galactosidase;TLR, toll-like receptor; WB, western blotting.Cigarette smoke (CS)-induced mitochondrial damage with increased reactive oxygen species (ROS) production has been implicated in COPD pathogenesis by accelerating senescence. Mitophagy may play a pivotal role for removal of CS-induced damaged mitochondria, and the PINK1 (PTEN-induced putative kinase 1)-PARK2 pathway has been proposed as a crucial mechanism for mitophagic degradation. Therefore, we sought to investigate to determine if PINK1-PARK2-mediated mitophagy is involved in the regulation of CS extract (CSE)-induced cell senescence and in COPD pathogenesis. Mitochondrial damage, ROS production, and cell senescence were evaluated in primary human bronchial epithelial cells (HBEC). Mitophagy was assessed in BEAS-2B cells stably expressing EGFP-LC3B, using confocal microscopy to measure colocalization between TOMM20-stained mitochondria and EGFP-LC3B dots as a representation of autophagosome formation. To elucidate the involvement of PINK1 and PARK2 in mitophagy, knockdown and overexpression experiments were performed. PINK1 and PARK2 protein levels in lungs from patients were evaluated by means of lung homogenate and immunohistochemistry. We demonstrated that CSE-induced mitochondrial damage was accompanied by increased ROS production and HBEC senescence. CSE-induced mitophagy was inhibited by PINK1 and PARK2 knockdown, resulting in enhanced mitochondrial ROS production and cellular senescence in HBEC. Evaluation of protein levels demonstrated decreased PARK2 in COPD lungs compared with non-COPD lungs. These results suggest that PINK1-PARK2 pathway-mediated mitophagy plays a key regulatory role in CSE-induced mitochondrial ROS production and cellular senescence in HBEC. Reduced PARK2 expression levels in COPD lung suggest that insufficient mitophagy is a part of the pathogenic sequence of COPD.

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“…84 Similar to BNIP3L, the related BH3-only mitochondrial protein BNIP3 also contains an LIR, which promotes binding to Atg8 family members LC3B and GABARAPL2. 86 BNIP3 is a pro-apoptotic member of the BCL2 family that is upregulated during heart failure and contributes to loss of myocardial cells during ischemia/reperfusion. 87 BNIP3 promotes autophagy and mitochondrial turnover under hypoxic conditions in a HIF1A-dependent manner; [88][89][90] therefore, it may play a role in mitochondrial turnover in HSCs, a possibility that remains to be explored.…”

Section: Receptors For Mitophagymentioning

confidence: 99%

Mitophagy in hematopoietic stem cells

Joshi

Kundu

2013

Autophagy

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Microtubule-associated Protein 1 Light Chain 3 (LC3) Interacts with Bnip3 Protein to Selectively Remove Endoplasmic Reticulum and Mitochondria via Autophagy

Cited by 607 publications

References 45 publications

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Potential function for the Huntingtin protein as a scaffold for selective autophagy

PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis

Mitophagy in hematopoietic stem cells

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