CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane

Mi, Na; Chen, Yang; Wang, Shuai; Chen, Mengran; Zhao, Mingkun; Yang, Guang; Ma, Mingyu; Su, Qian; Luo, Sai; Shi, Jingwen; Xu, Jun; Guo, Qiang; Gao, Ning; Sun, Yujie; Chen, Zhucheng; Yu, Li

doi:10.1038/ncb3215

Cited by 120 publications

(124 citation statements)

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“…In addition, the B. cenocepacia T6SS effector TecA mediates the deamidation of RHOA in murine cells [32]. RHOA is well known for its ability to induce actin-derived stress fibers and focal adhesions [61], and it also promotes the activation of LIM kinases, which inhibit CFL1 via phosphorylation [62,63]. …”

Section: Discussionmentioning

confidence: 99%

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Krause¹,

Caution²,

Badr³

et al. 2018

Autophagy

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CASP4/caspase-11-dependent inflammasome activation is important for the clearance of various Gram-negative bacteria entering the host cytosol. Additionally, CASP4 modulates the actin cytoskeleton to promote the maturation of phagosomes harboring intracellular pathogens such as Legionella pneumophila but not those enclosing nonpathogenic bacteria. Nevertheless, this non-inflammatory role of CASP4 regarding the trafficking of vacuolar bacteria remains poorly understood. Macroautophagy/autophagy, a catabolic process within eukaryotic cells, is also implicated in the elimination of intracellular pathogens such as Burkholderia cenocepacia. Here we show that CASP4-deficient macrophages exhibit a defect in autophagosome formation in response to B. cenocepacia infection. The absence of CASP4 causes an accumulation of the small GTPase RAB7, reduced colocalization of B. cenocepacia with LC3 and acidic compartments accompanied by increased bacterial replication in vitro and in vivo. Together, our data reveal a novel role of CASP4 in regulating autophagy in response to B. cenocepacia infection.

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Section: Discussionmentioning

confidence: 99%

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Krause¹,

Caution²,

Badr³

et al. 2018

Autophagy

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“…The puncta detected by the authors are also positive for several branched actin network markers, namely: actindynamizing protein, CFL (cofilin), actin-capping protein, CAPZ, or the aforementioned ARP2/3 complex. Due to the CAPZ role as a negative regulator of actin polymerization and branching, the knockdown of the CAPZ protein gives a similar result 9 as the expression of the positive actin nucleation regulator, JMY. 7 Depletion of CAPZ causes formation of LC3-and ZFYVE1-positive elongated filamentous structures, providing evidence that CAPZ also controls the actin network from the inside of the phagophore.…”

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confidence: 57%

“…Certainly this can happen. As Mi et al, 9 demonstrate by using super resolution and electron microscopy, actin is present inside the central cavity of newly-formed autophagosomes (Fig. 1Cvi).…”

mentioning

confidence: 83%

“…3 However, despite strong evidence of actin cytoskeleton participation in some early steps of autophagy, the precise role of actin in autophagosome formation remained unclear, leaving open questions regarding whether actin filaments serve only as motors transporting required components to the autophagosome formation site or whether actin filaments are also involved in membrane invagination, as demonstrated for the formation of endocytic vesicles. 6 Three studies, by Mi et al, Kast et al, and Coutts and Thangue, [7][8][9] have now answered these questions by proving that actin nucleation actually shapes autophagosomes.…”

mentioning

confidence: 99%

“…The omegasome is a structure rich in another phosphoinositide, PtdIns3P. 17 The authors 9 found that CAPZ binds to PtdIns3P and that it stimulates uncapping of actin and promotes actin network construction (see description for Fig. 1Ciii-v).…”

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confidence: 99%

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Role of actin in shaping autophagosomes

Zientara‐Rytter

Subramani

2016

Autophagy

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One of the main unanswered questions regarding the early steps of macroautophagy/autophagy is the mechanism of membrane-modeling events required for autophagosome formation. Three independent studies have recently revealed an actin cytoskeleton involvement in this process, providing significant details regarding the role of actin in nucleation events both inside and outside the phagophore membrane during its expansion and assembly.

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Phosphoinositide‐binding proteins in autophagy

Lystad

Simonsen

2016

FEBS Letters

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Edited by Wilhelm JustPhosphoinositides represent a very small fraction of membrane phospholipids, having fast turnover rates and unique subcellular distributions, which make them perfect for initiating local temporal effects. Seven different phosphoinositide species are generated through reversible phosphorylation of the inositol ring of phosphatidylinositol (PtdIns). The negative charge generated by the phosphates provides specificity for interaction with various protein domains that commonly contain a cluster of basic residues. Examples of domains that bind phosphoinositides include PH domains, WD40 repeats, PX domains, and FYVE domains. Such domains often display specificity toward a certain species or subset of phosphoinositides. Here we will review the current literature of different phosphoinositide-binding proteins involved in autophagy.Keywords: autophagy; FYVE; PH; phosphoinositide; PX AutophagyAutophagy is the process by which cellular components are transported to the lysosome (or the yeast vacuole) for degradation to provide cellular homeostasis and quality control. There are three main forms of autophagy, namely microautophagy, which involves a direct engulfment of cytosolic cargo by the endosomal or lysosomal/vacuolar membrane, chaperone-mediated autophagy (CMA), involving lysosomal translocation of cytosolic protein cargo, and macroautophagy, a vesicle transport pathway where cargo is sequestered into double-membrane autophagosomes which undergo fusion with endosomes and/or the lysosome/vacuole. Autophagy is induced upon cellular stress (e.g., starvation) to facilitate cell survival by providing building blocks that can be used to produce essential molecules and generate energy. However, autophagy also serves an important quality control function under basal conditions by selective clearance of damaged or dysfunctional cellular components [1].Macroautophagy (hereafter autophagy) involves nucleation of a phagophore membrane (also called the isolation membrane) from specific phosphatidyl inositol 3-phosphate (PtdIns3P)-enriched structures, called the phagophore assembly site (PAS, a peri-vacuolar structure) in yeast and the omegasome (associated with the endoplasmic reticulum, ER) in mammals. Typically, there is only a single PAS in yeast, while several ER-associated omegasomes are detected upon Abbreviations ALFY, autophagy-linked FYVE protein; Arf6, adenosine diphosphate ribosylation factor 6; ATG, autophagy-related; BATS, biotin and thiamin synthesis-associated domain; Cvt, cytoplasm-to-vacuole; DFCP1, double FYVE-containing protein 1; ER, endoplasmic reticulum; FYCO1, FYVE and coiled-coil domain-containing 1; GRAM, glycosyltransferases Rab-like GTPase activators and myotubularins; HOPS, homotypic fusion and protein sorting; Hsv2, homologous with swollen vacuole phenotype 2; LIR, LC3-interacting region; MTMR3, myotubularin-related protein 3; mTORC1, mechanistic target of rapamycin complex 1; PA, phosphatidic acid; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide-dependent protein kinase ...

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CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane

Cited by 120 publications

References 56 publications

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Role of actin in shaping autophagosomes

Phosphoinositide‐binding proteins in autophagy

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