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Autophagy of an Amyloid-Like Translational Repressor Regulates Meiotic Exit

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Autophagy of an Amyloid-Like Translational Repressor Regulates Meiotic Exit Short Article Autophagy of an Amyloid-like Translational Repressor Regulates Meiotic Exit Highlights Authors d Autophagy is required for meiotic exit Fei Wang, Rudian Zhang, Wenzhi Feng, ..., Jiajia Li, d Autophagy prevents additional rounds of chromosome Vladimir Denic, Soni Lacefield segregation after meiosis II Correspondence d Autophagy degrades the amyloid-like translational repressor Rim4 in meiosis II [email protected] (F.W.), [email protected] (V.D.), [email protected] (S.L.) d Inhibition of autophagy leads to aberrant persistence of meiotic regulators In Brief Wang et al. report that autophagy promotes meiotic termination by degrading Rim4, an amyloid-like translational repressor whose timed clearance in meiosis II regulates protein production from its mRNA targets. In the absence of autophagy, cells fail to exit meiosis and undergo additional rounds of chromosome segregation after meiosis II. Wang et al., 2020, Developmental Cell 52, 141–151 January 27, 2020 ª 2019 Elsevier Inc. https://doi.org/10.1016/j.devcel.2019.12.017 Developmental Cell Short Article Autophagy of an Amyloid-like Translational Repressor Regulates Meiotic Exit Fei Wang,1,* Rudian Zhang,1 Wenzhi Feng,1 Dai Tsuchiya,2,4 Olivia Ballew,2 Jiajia Li,1 Vladimir Denic,3,* and Soni Lacefield2,5,* 1Department of Internal Medicine, Center for Autophagy Research, UT Southwestern Medical Center, Dallas, TX, USA 2Department of Biology, Indiana University, Bloomington, IN, USA 3Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA 4Present address: Stowers Institute for Medical Research, Kansas City, MO, USA 5Lead Contact *Correspondence: [email protected] (F.W.), [email protected] (V.D.), [email protected] (S.L.) https://doi.org/10.1016/j.devcel.2019.12.017 SUMMARY events during different stages of sexual reproduction and early stages of development (Yin et al., 2016). For example, following We explored the potential for autophagy to regulate oocyte fertilization in mice, flies, and worms, autophagy selec- budding yeast meiosis. Following pre-meiotic DNA tively targets paternal mitochondria for destruction to enable replication, we blocked autophagy by chemical maternal inheritance of mtDNA (Politi et al., 2014; Rojansky inhibition of Atg1 kinase or engineered degradation et al., 2016; Sato and Sato, 2011). Autophagy is also responsible of Atg14 and observed homologous chromosome for targeted elimination of P granule ribonucleoproteins during segregation followed by sister chromatid separation; early embryonic cell divisions in worms to help restrict primordial germline specification (Zhang et al., 2009). Lastly, preimplantation cells then underwent additional rounds of spindle for- development in early mouse embryos is arrested by mutations mation and disassembly without DNA re-replication, that disrupt autophagy (Tsukamoto et al., 2008). leading to aberrant chromosome segregation. Anal- During sexual reproduction in budding yeast, starvation gener- ysis of cell-cycle regulators revealed that autophagy ates a key signal for pre-meiotic DNA replication in diploid cells. inhibition prevents meiosis II-specific expression of This meiosis-initiating event is followed by two divisions in which Clb3 and leads to the aberrant persistence of Clb1 homologous chromosomes segregate (meiosis I) and sister chro- and Cdc5, two substrates of a meiotic ubiquitin ligase matids separate (meiosis II) to enable haploid gamete formation activated by Ama1. Lastly, we found that during by an overlapping sporulation program (Neiman, 2011). Auto- meiosis II, autophagy degrades Rim4, an amyloid- phagy mutants lacking key autophagy-related factors (Atg) are like translational repressor whose timed clearance unable to form gametes because they fail to undergo the meiotic regulates protein production from its mRNA targets, divisions in response to starvation (Enyenihi and Saunders, 2003; Piekarska et al., 2010; Sarkar et al., 2014; Straub et al., 1997; Wen which include CLB3 and AMA1. Strikingly, engineered et al., 2016). We hypothesized that autophagy plays an additional, Clb3 or Ama1 production restored meiotic termination regulatory role during yeast meiotic divisions. This idea was in the absence of autophagy. Thus, autophagy de- inspired by evidence from a genome-wide analysis of translation stroys a master regulator of meiotic gene expression during meiosis I and II that showed enhanced synthesis of Atg8 to enable irreversible meiotic exit. (Brar et al., 2012), a factor whose abundance is known to be size limiting for autophagosomes (Xie et al., 2008). Here, we have found that inactivation of two key components INTRODUCTION of the autophagy machinery—Atg1 and Atg14—during prophase I results in a deregulation of cell-cycle events in which chromo- Macroautophagy (herein called autophagy) is a highly conserved somes continue to segregate following meiosis II and gameto- cellular degradation process that removes protein aggregates, genesis is aborted. Analysis of several cell-cycle regulators led damaged organelles, and other potentially toxic structures (Yin us to discover that with Atg1 inhibition, there was a defect in au- et al., 2016). During autophagy, cytoplasmic material becomes tophagic degradation of Rim4, an amyloid-like translational encapsulated into double-membrane vesicles (autophagosomes) repressor of many mRNAs during meiosis II (Berchowitz et al., that subsequently fuse with lysosomes, thus delivering their cargo 2013). Strikingly, the effects of Atg1 inhibition on meiosis were for degradation. Autophagy was originally discovered as a starva- suppressed by engineered protein expression of two Rim4 tion response that recycles macromolecules to maintain energy mRNA targets, the cyclin Clb3 and Ama1, a meiosis-specific stores and biosynthesis of essential components. Beyond its activator of the APC/C ubiquitin ligase. These results provide a role as a stress response, autophagy has emerged in recent years mechanistic explanation for how autophagy drives exit from as a versatile degradation mechanism for controlling key cellular meiosis. Developmental Cell 52, 141–151, January 27, 2020 ª 2019 Elsevier Inc. 141 +β-estradiol A +/- 1-NM-PP1 Meiosis Entry Pre-meiotic S Prophase I Prometaphase I Metaphase I Anaphase I Metaphase II Anaphase II B ATG1 cell + 1-NM-PP1 GFP-Tub1 Zip1-GFP Spc42-mCherry -10 0 50 60 80 110 120 170 600 Prophase I Prophase I Metaphase I Anaphase I Spindle Metaphase II Anaphase II Spindle Exit Breakdown Breakdown C atg1-as cell + 1-NM-PP1 -10 30 70 170 190 240 250 260 270 290 GFP-Tub1 Zip1-GFP Spc42-mCherry 300 310 330 340 350 360 370 390 400 410 430 440 460 490 520 580 630 670 700 730 D E * * Two Divisions Additional SPBs/ spindles Arrested Died Percent of Cells Percent of Cells 1NM-PP1: - + - + + 56789 ATG1 atg1-as atg1-as Number of Spindle Pole Bodies + ATG1 FG H * Two Divisions Additional SPBs/ spindles Percent of Cells Percent of Cells Percent of Cells 1234 123456789 17 Number of Additional Rounds of Number of Additional Rounds of Spindle ATG14 Spindle Pole Body Accumulations Elongation and Breakdown After Meiosis II N-deg-ATG14 Figure 1. Autophagy Inhibition Causes Additional Rounds of Spindle Formation and Breakdown after Meiosis II (A) Cartoon showing cell-cycle stages of budding yeast meiosis with synchronization by NDT80-in and release from prophase I arrest by b-estradiol addition. Unless indicated otherwise, 1-NM-PP1 was always added to meiotic cells at the time of arrest release. (B) Representative time-lapse images of a wild-type (ATG1) cell undergoing synchronized meiosis in the presence of 1-NM-PP1. Also pictured, a brightfield image of spores at the end of the time lapse. Blue arrowhead shows Zip1-GFP. Scale bar, 5 mm. (legend continued on next page) 142 Developmental Cell 52, 141–151, January 27, 2020 RESULTS events culminating in the formation of four terminal haploid prog- eny packaged into spores (Figures 1B and S1B; Video S1). By Autophagy Inhibition Results in Aberrant Cycles of contrast, the 1-NM-PP1 treatment of Atg1-as led cells to a some- Additional Spindle Formation and Breakdown Following what slower progression through meiosis I and meiosis II, followed Meiosis II by the more striking formation of supernumerary SPBs that medi- As deletion of core autophagy genes is known to preclude entry ated additional rounds of spindle formation and breakdown (Fig- into the meiotic divisions (Enyenihi and Saunders, 2003; Piekar- ures 1C, 1D, and S1C; Video S2). Cells accumulated between ska et al., 2010; Sarkar et al., 2014; Straub et al., 1997; Wen et al., 5–9 SPBs over time and underwent between 1–17 additional aber- 2016), we used chemical genetics to inhibit the Atg1 kinase rant cycles of spindle elongation through spindle breakdown (Fig- following completion of pre-meiotic DNA replication and at the ures 1E–1G). The additional cycles highly varied in duration, but on end of prophase I. This approach relied on a mutation in the average were similar to the durations of meiosis I and meiosis II Atg1 ATP-binding site known to enable robust inhibition of auto- (Figures S1C-S1E). We confirmed that this phenotype was in phagy by 1-NM-PP1, a cell-permeable ATP analog (Blethrow fact the consequence of Atg1 kinase loss by achieving rescue us- et al., 2004; Kamada et al., 2000; Kamber et al., 2015). We intro- ing a transgenic wild-type ATG1 (Figure 1D). duced Atg1-as into a system for inducible expression of NDT80 Atg1 kinase inhibition could prevent normal termination of (NDT80-in),
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