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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    • "This targeting of RNA granules to the vacuole by autophagy was referred as " granulophagy " and may provide a mechanism for efficient PBs/SGs clearance, regulating their abundance during stress and development, serving in parallel as a means for the mass degradation of mRNA molecules that reside inside them (Buchan et al., 2013). A similar mechanism has been found to occur during C. elegans embryonic development, where germ-line specific mRNPs (P-granules) are selectively removed from somatic cells through autophagy (Zhang et al., 2009). "
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    ABSTRACT: Messenger RNA (mRNA) turnover that determines the lifetime of cytoplasmic mRNAs is a means to control gene expression under both normal and stress conditions, whereas its impact on ageing and age-related disorders has just become evident. Gene expression control is achieved at the level of the mRNA clearance as well as mRNA stability and accessibility to other molecules. All these processes are regulated by cis-acting motifs and trans-acting factors that determine the rates of translation and degradation of transcripts. Specific messenger RNA granules that harbor the mRNA decay machinery or various factors, involved in translational repression and transient storage of mRNAs, are also part of the mRNA fate regulation. Their assembly and function can be modulated to promote stress resistance in adverse conditions and over time affect the ageing process and the lifespan of the organism. Here, we provide insights into the complex relationships of ageing modulators and mRNA turnover mechanisms.
    Mechanisms of ageing and development 10/2015; 152. DOI:10.1016/j.mad.2015.09.006 · 3.40 Impact Factor
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    • "LGG-2 RNAi treatment was lethal in mutants carrying a loss-of-function mutation in daf-2, the C. elegans insulin-like tyrosine kinase receptor that triggers constitutive dauer entry (Meléndez et al., 2003). Furthermore, LGG-2-depleted embryos accumulate P-granule components in the somatic cells (Zhang et al., 2009). In lgg-2(tm5755) mutant embryos, LGG-1 was still recruited around sperm organelles and appeared clustered in the early embryos (Manil-Ségalen et al., 2014). "
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    ABSTRACT: Macroautophagic degradation of sperm-inherited organelles prevents paternal mitochondrial DNA transmission in C. elegans. The recruitment of autophagy markers around sperm mitochondria has also been observed in mouse and fly embryos but their role in degradation is debated. Both worm Atg8 ubiquitin-like proteins, LGG-1/GABARAP and LGG-2/LC3, are recruited around sperm organelles after fertilization. Whereas LGG-1 depletion affects autophagosome function, stabilizes the substrates and is lethal, we demonstrate that LGG-2 is dispensable for autophagosome formation but participates in their microtubule-dependent transport toward the pericentrosomal area prior to acidification. In the absence of LGG-2, autophagosomes and their substrates remain clustered at the cell cortex, away from the centrosomes and their associated lysosomes. Thus, the clearance of sperm organelles is delayed and their segregation between blastomeres prevented. This allowed us to reveal a role of the RAB-5/RAB-7 GTPases in autophagosome formation. In conclusion, the major contribution of LGG-2 in sperm-inherited organelle clearance resides in its capacity to mediate the retrograde transport of autophagosomes rather than their fusion with acidic compartments: a potential key function of LC3 in controlling the fate of sperm mitochondria in other species. © 2015. Published by The Company of Biologists Ltd.
    Development 05/2015; 142(9):1705-16. DOI:10.1242/dev.117879 · 6.46 Impact Factor
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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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