SEPA-1 Mediates the Specific Recognition and Degradation of P Granule Components by Autophagy in C. elegans

National Institute of Biological Sciences, Beijing 102206, P.R. China.
Cell (Impact Factor: 32.24). 02/2009; 136(2):308-21. DOI: 10.1016/j.cell.2008.12.022
Source: PubMed


How autophagy, an evolutionarily conserved intracellular catabolic system for bulk degradation, selectively degrades protein aggregates is poorly understood. Here, we show that several maternally derived germ P granule components are selectively eliminated by autophagy in somatic cells during C. elegans embryogenesis. The activity of sepa-1 is required for the degradation of these P granule components and for their accumulation into aggregates, termed PGL granules, in autophagy mutants. SEPA-1 forms protein aggregates and is also a preferential target of autophagy. SEPA-1 directly binds to the P granule component PGL-3 and also to the autophagy protein LGG-1/Atg8. SEPA-1 aggregates consistently colocalize with PGL granules and with LGG-1 puncta. Thus, SEPA-1 functions as a bridging molecule in mediating the specific recognition and degradation of P granule components by autophagy. Our study reveals a mechanism for preferential degradation of protein aggregates by autophagy and emphasizes the physiological significance of selective autophagy during animal development.

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Available from: Kai Zhang, Nov 14, 2014
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    • "VBH-1 was also localized into large aggregates in both somatic and germline blastomeres during early embryogenesis after heat shock. The aggregates in somatic blastomeres are not P granules because these are asymmetrically inherited to the germline blastomeres and further disassembled and degraded through autophagy in somatic blastomeres [67], [68]. One important difference between the aggregates formed in the gonad and those observed in early embryos is that in the latter, VBH-1 did not perfectly overlap with CGH-1; however, these proteins are closely associated. "
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    ABSTRACT: For several years, DEAD box RNA helicase Vasa (DDX4) has been used as a bona fide germline marker in different organisms. C. elegans VBH-1 is a close homolog of the Vasa protein, which plays an important role in gametogenesis, germ cell survival and embryonic development. Here, we show that VBH-1 protects nematodes from heat shock and oxidative stress. Using the germline-defective mutant glp-4(bn2) we found that a potential somatic expression of vbh-1 might be important for stress survival. We also show that the VBH-1 paralog LAF-1 is important for stress survival, although this protein is not redundant with its counterpart. Furthermore, we observed that the mRNAs of the heat shock proteins hsp-1 and sip-1 are downregulated when vbh-1 or laf-1 are silenced. Previously, we reported that in C. elegans, VBH-1 was primarily expressed in P granules of germ cells and in the cytoplasm of all blastomeres. Here we show that during stress, VBH-1 co-localizes with CGH-1 in large aggregates in the gonad core and oocytes; however, VBH-1 aggregates do not overlap with CGH-1 foci in early embryos under the same conditions. These data demonstrate that, in addition to the previously described role for this protein in the germline, VBH-1 plays an important role during the stress response in C. elegans through the potential direct or indirect regulation of stress response mRNAs.
    PLoS ONE 05/2014; 9(5):e97924. DOI:10.1371/journal.pone.0097924 · 3.23 Impact Factor
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    • "their strict dependence on SEPA-1 for the formation of aggregates. PGL-1 directly associates with PGL-3, and PGL-3 interacts with SEPA-1 (Zhang et al., 2009). Arginine methylation of the RGG domains of PGL-1 and PGL-3 may prevent the formation of PGL-1 and PGL-3 aggregates. "
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    ABSTRACT: The selective degradation of intracellular components by autophagy involves sequential interactions of the cargo with a receptor, which also binds the autophagosomal protein Atg8 and a scaffold protein. Here, we demonstrated that mutations in C. elegans epg-11, which encodes an arginine methyltransferase homologous to PRMT1, cause the defective removal of PGL-1 and PGL-3 (cargo)-SEPA-1 (receptor) complexes, known as PGL granules, from somatic cells during embryogenesis. Autophagic degradation of the PGL granule scaffold protein EPG-2 and other protein aggregates was unaffected in epg-11/prmt-1 mutants. Loss of epg-11/prmt-1 activity impairs the association of PGL granules with EPG-2 and LGG-1 puncta. EPG-11/PRMT-1 directly methylates arginines in the RGG domains of PGL-1 and PGL-3. Autophagic removal of PGL proteins is impaired when the methylated arginines are mutated. Our study reveals that posttranslational arginine methylation regulates the association of the cargo-receptor complex with the scaffold protein, providing a mechanism for modulating degradation efficiency in selective autophagy.
    Molecular cell 10/2013; 52(3). DOI:10.1016/j.molcel.2013.09.014 · 14.02 Impact Factor
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    • "An important corollary—that primary defects in ribostasis should not only increase RNP aggregation but should also influence the protein-folding pathways—remains to be rigorously tested, for instance, by examining the possible activation of unfolded protein response following perturbations to RNA regulatory pathways. Crosstalk between proteostasis and ribostasis is also evident in the emerging role of autophagy in clearing RNP aggregates from cells (Zhang et al., 2009; Buchan et al., 2013). Thus, it is expected that impairment in autophagy through either agerelated decline or genetic mutation (e.g., VCP mutations) not only perturbs proteostasis, but also disrupts the normal clearance of stress granules, resulting in perturbed ribostasis. "
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    ABSTRACT: The molecular processes that contribute to degenerative diseases are not well understood. Recent observations suggest that some degenerative diseases are promoted by the accumulation of nuclear or cytoplasmic RNA-protein (RNP) aggregates, which can be related to endogenous RNP granules. RNP aggregates arise commonly in degenerative diseases because RNA-binding proteins commonly self-assemble, in part through prion-like domains, which can form self-propagating amyloids. RNP aggregates may be toxic due to multiple perturbations of posttranscriptional control, thereby disrupting the normal ‘‘ribostasis’’ of the cell. This suggests that understanding and modulating RNP assembly or clearance may be effective approaches to developing therapies for these diseases.
    Cell 08/2013; 154(4). DOI:10.1016/j.cell.2013.07.038 · 32.24 Impact Factor
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