Acetylated microtubules are required for fusion of autophagosomes with lysosomes

Xie, Rui; Nguyen, Susan; McKeehan, Wallace L.; Liu, Leyuan

doi:10.1186/1471-2121-11-89

Cited by 181 publications

(177 citation statements)

References 39 publications

(75 reference statements)

Supporting

Mentioning

165

Contrasting

Order By: Relevance

“…A potential molecular mechanism by which WDR47 regulates autophagy might be through its interaction with the light chain of MAP8 (also known as MAP1S) (23). In a similar way to MAP8 (45), WDR47 might bridge the autophagy machinery, in particular, LC3-II-bound autophagosomes, with microtubules. Unlike other cells of the mammalian system, postmitotic neurons are more vulnerable to damage from cellular debris and thus, would require a well-regulated degradation pathway.…”

Section: Discussionmentioning

confidence: 99%

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

Kannan

Bayam

Wagner

et al. 2017

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

110

View full text Add to dashboard Cite

The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.WD40-repeat proteins | corpus callosum agenesis | microcephaly | neurogenesis | autophagy T he function of WD40-repeat (WDR)-containing proteins, one of the largest eukaryotic protein families, is largely unknown. Their importance is, however, evident based on their highly conserved repeating units from bacteria to mammals (1), commonly made of seven repetitive blades of 40 amino acids that end with a tryptophan-aspartic acid dipeptide at the C terminus.As shown by crystallography studies, including the crystal structure of the beta gamma dimer of the G-protein transducin (2), a classical WDR protein, all WDR proteins are predicted to fold into a circularized beta-propeller structure, serving as a rigid platform (or scaffold) for protein-protein interactions by providing many stable and symmetrical surfaces (3, 4). One reason why WDR domains may have been less studied than other common domains, such as kinases or PDZ or SH3 domains (3), is that no WDR domain has yet been found with catalytic activity (3), but this does not mean that the scaffold domains are less important. To the contrary, their serving as a platform for multiple enzymatic reactions and signaling events is highly significant (5).In recent years, human genetic studies have also begun to recognize the importance of WDR gen...

show abstract

Section: Discussionmentioning

confidence: 99%

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

Kannan

Bayam

Wagner

et al. 2017

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

110

View full text Add to dashboard Cite

show abstract

“…Autophagosomes migrate along acetylated microtubules to fuse with lysosomes to form autolysosomes in which substrates are degraded (Fig. 1H) (Mizushima et al ., 2008; Xie et al ., 2010). Fibronectin‐containing late endosome may also fuses with autophagosome to form amphisome, and then fuses with lysosome to form autolysosomes (Fig.…”

Section: Introductionmentioning

confidence: 99%

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Zou

Fei

et al. 2016

Aging Cell

Self Cite

View full text Add to dashboard Cite

SummaryAutophagy is a cellular process that executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Microtubule‐associated protein MAP1S interacts with autophagy marker LC3 and positively regulates autophagy flux. LC3 binds with fibronectin mRNA and facilitates its translation. The synthesized fibronectin protein is exported to cell surface to initiate the assembly of fibronectin extracellular matrix. Fibronectin is degraded in lysosomes after it is engulfed into cytosol via endocytosis. Here, we show that defects in MAP1S‐mediated autophagy trigger oxidative stress, sinusoidal dilation, and lifespan reduction. Overexpression of LC3 in wild‐type mice increases the levels of fibronectin and γ‐H2 AX, a marker of DNA double‐strand breakage. LC3‐induced fibronectin is efficiently degraded in lysosomes to maintain a balance of fibronectin levels in wild‐type mice so that the mice live a normal term of lifespan. In the LC3 transgenic mice with MAP1S deleted, LC3 enhances the synthesis of fibronectin but the MAP1S depletion causes an impairment of the lysosomal degradation of fibronectin. The accumulation of fibronectin protein promotes liver fibrosis, induces an accumulation of cell population at the G0/G1 stage, and further intensifies oxidative stress and sinusoidal dilatation. The LC3‐induced overexpression of fibronectin imposes stresses on MAP1S‐deficient mice and dramatically reduces their lifespans. Therefore, MAP1S‐mediated autophagy plays an important role in maintaining mouse lifespan especially in the presence of extra amount of fibronectin.

show abstract

“…Paclitaxel, another microtubule stabilizer, ameliorates motor impairment while improving fast axonal transport and axonal morphology in tau transgenic mice [202]. Conflicting reports, however, have emerged regarding the role of paclitaxel in autophagy induction [203,204]. Through its stabilization of microtubules, paclitaxel may be a viable therapy for enhancing autophagic transport and fusion.…”

Section: Trehalosementioning

confidence: 99%

Promoting Autophagic Clearance: Viable Therapeutic Targets in Alzheimer's Disease

Friedman

Qureshi

2015

Neurotherapeutics

View full text Add to dashboard Cite

Many neurodegenerative disorders are characterized by the aberrant accumulation of aggregate-prone proteins. Alzheimer's disease (AD) is associated with the buildup of β-amyloid peptides and tau, which aggregate into extracellular plaques and neurofibrillary tangles, respectively. Multiple studies have linked dysfunctional intracellular degradation mechanisms with AD pathogenesis. One such pathway is the autophagy-lysosomal system, which involves the delivery of large protein aggregates/inclusions and organelles to lysosomes through the formation, trafficking, and degradation of double-membrane structures known as autophagosomes. Converging data suggest that promoting autophagic degradation, either by inducing autophagosome formation or enhancing lysosomal digestion, provides viable therapeutic strategies. In this review, we discuss compounds that can augment autophagic clearance and may ameliorate disease-related pathology in cell and mouse models of AD. Canonical autophagy induction is associated with multiple signaling cascades; on the one hand, the best characterized is mammalian target of rapamycin (mTOR). Accordingly, multiple mTOR-dependent and mTORindependent drugs that stimulate autophagy have been tested in preclinical models. On the other hand, there is a growing list of drugs that can enhance the later stages of autophagic flux by stabilizing microtubule-mediated trafficking, promoting lysosomal fusion, or bolstering lysosomal enzyme function. Although altering the different stages of autophagy provides many potential targets for AD therapeutic interventions, it is important to consider how autophagy drugs might also disturb the delicate balance between autophagosome formation and lysosomal degradation.

show abstract

Acetylated microtubules are required for fusion of autophagosomes with lysosomes

Cited by 181 publications

References 39 publications

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Promoting Autophagic Clearance: Viable Therapeutic Targets in Alzheimer's Disease

Contact Info

Product

Resources

About