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Quality-Control Mechanisms Targeting Translationally Stalled and C-Terminally Extended Poly(GR) Associated with ALS/FTD

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Quality-Control Mechanisms Targeting Translationally Stalled and C-Terminally Extended Poly(GR) Associated with ALS/FTD Quality-control mechanisms targeting translationally stalled and C-terminally extended poly(GR) associated with ALS/FTD Shuangxi Lia, Zhihao Wua, Ishaq Tantraya,YuLia, Songjie Chenb, Jason Dongc, Steven Glynnd, Hannes Vogela, Michael Snyderb, and Bingwei Lua,1 aDepartment of Pathology, Stanford University School of Medicine, Stanford, CA 94305; bDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305; cElectrical Engineering and Computer Sciences, University of California, Berkeley, CA 94305; and dDepartment of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794 Edited by Lily Yeh Jan, University of California, San Francisco, CA, and approved August 26, 2020 (received for review March 24, 2020) Maintaining the fidelity of nascent peptide chain (NP) synthesis is in translation termination activity (6–8). In response, the con- essential for proteome integrity and cellular health. Ribosome- served ribosome-associated quality control (RQC) complex is associated quality control (RQC) serves to resolve stalled transla- recruited to stalled ribosomes to target the aberrant translation tion, during which untemplated Ala/Thr residues are added C ter- products and the template mRNAs for degradation. Studies in minally to stalled peptide, as shown during C-terminal Ala and Thr yeast showed that NPs on stalled ribosomes can be modified addition (CAT-tailing) in yeast. The mechanism and biological ef- while still attached to 60S subunits, in a C-terminal Ala and Thr fects of CAT-tailing–like activity in metazoans remain unclear. Here addition (CAT-tailing) process (9). So far CAT-tailing has been we show that CAT–tailing-like modification of poly(GR), a dipep- studied mainly using artificial substrates and under conditions tide repeat derived from amyotrophic lateral sclerosis with fronto- that interfere with the degradation of the stalled NPs. The temporal dementia (ALS/FTD)-associated GGGGCC (G4C2) repeat physiological role of CAT-tailing in the context of intact RQC expansion in C9ORF72, contributes to disease. We find that pol- remains unsettled. It may induce the heat-shock response (10), y(GR) can act as a mitochondria-targeting signal, causing some push lysine residues of stalled NPs out of the ribosome exit poly(GR) to be cotranslationally imported into mitochondria. How- tunnel (11), or drive degradation of stalled NPs on and off the NEUROSCIENCE ever, poly(GR) translation on mitochondrial surface is frequently ribosomes (12). Recent studies in yeast and metazoans empha- – stalled, triggering RQC and CAT-tailing like C-terminal extension sized the importance of RQC and CAT-tailing–like process in (CTE). CTE promotes poly(GR) stabilization, aggregation, and tox- maintaining mitochondrial function by protecting the integrity of Drosophila icity. Our genetic studies in uncovered an important nuclear-encoded mitochondrial proteins that are cotranslation- role of the mitochondrial protease YME1L in clearing poly(GR), ally imported (7, 13). Since failure in the timely removal of CAT- revealing mitochondria as major sites of poly(GR) metabolism. tailed proteins can cause proteotoxicity in yeast (14–16), and Moreover, the mitochondria-associated noncanonical Notch sig- defective RQC is linked to neurodegeneration in mouse mutants naling pathway impinges on the RQC machinery to restrain pol- (17, 18) and PD models (7), it is important to elucidate the y(GR) accumulation, at least in part through the AKT/VCP axis. The conserved actions of YME1L and noncanonical Notch signaling in animal models and patient cells support their fundamental in- Significance volvement in ALS/FTD. Amyotrophic laterosclerosis (ALS) is a rapidly progressing C9-ALS/FTD | ribosome-associated quality control | CAT-tailing | YME1L | neurological disease that robs patients’ motor functions. De- Notch spite intensive research, molecular events that initiate the disease are poorly understood. Expansion of G4C2 repeats in the C9orf72 gene causes ALS with frontotemporal dementia, berrant protein aggregation manifesting failed cellular one of the most common forms of ALS. Increasing evidence protein homeostasis (proteostasis) is a defining feature of A suggests that dipeptides translated from G4C2 repeat tran- age-related neurodegenerative diseases (1, 2). These hallmark scripts, especially the arginine-containing poly(GR) and pol- aggregates include amyloid plaque in Alzheimer’s disease, Lewy y(PR), are particularly toxic. We found that translation of body in Parkinson’s disease (PD), neurofibrillary tangle in poly(GR) can occur on mitochondrial surface and is frequently tauopathies, poly-Q aggregate in Huntington’s diseas, and TDP- stalled, triggering ribosome-associated quality control and 43 aggregate in amyotrophic laterosclerosis (ALS). While ge- C-terminal extension, which promote poly(GR) aggregation netic mutations associated with the familial forms of diseases and toxicity. Genetic studies uncovered conserved roles of may cause protein misfolding and thus promote protein aggre- mitochondrial protease YME1L and noncanonical Notch sig- gation, less well understood is how the protein aggregates form naling in restraining poly(GR), offering insights into disease in the sporadic cases, which account for more than 90% of the pathogenesis and targets for therapeutic intervention. disease and which do not contain the familial mutations. Previous studies have focused heavily on aberrant folding and Author contributions: S.L., Z.W., I.T., and B.L. designed research; S.L., Z.W., I.T., Y.L., S.C., posttranslational modifications of fully synthesized, mature J.D., S.G., H.V., and B.L. performed research; M.S. contributed new reagents/analytic tools; proteins in mediating protein aggregation in aging or age-related S.L., Z.W., I.T., Y.L., S.C., J.D., S.G., H.V., and B.L. analyzed data; and S.L. and B.L. wrote diseases (3). Nevertheless, ubiquitination and degradation of the paper. nascent peptides (NPs) still associated with ribosomes is a The authors declare no competing interest. widespread phenomenon, indicating that quality control happens This article is a PNAS Direct Submission. early in the life cycle of cellular proteins (4, 5). During NP Published under the PNAS license. synthesis, the translating ribosomes could be stalled by a number 1To whom correspondence may be addressed. Email: [email protected]. of factors, including mRNA defects, strong mRNA secondary This article contains supporting information online at https://www.pnas.org/lookup/suppl/ structures, insufficient supply of aminoacyl-tRNAs, electrostatic doi:10.1073/pnas.2005506117/-/DCSupplemental. interaction between NPs and the ribosome exit tunnel, or deficit www.pnas.org/cgi/doi/10.1073/pnas.2005506117 PNAS Latest Articles | 1of12 Downloaded by guest on September 23, 2021 regulation and function of RQC and CAT-tailing in disease Fig. S1D), indicating specificity of YME1L regulation of pol- settings. However, the CAT-tailing–like C-terminal extension y(GR). Although most of the studies described above were done (CTE) of stalled NPs, the compositions of the CTEs, and the in male flies, female flies showed similar phenotypes and pol- pathological consequences of such CTE in disease settings have y(GR) regulation by YME1L (SI Appendix, Fig. S1E). Moreover, not been accessible for investigation due to the lack of identified manipulation of a number of other mitochondrial proteases, CAT-tailed substrates in metazoans, except in the case of the including Lon and Rhomboid, did not affect poly(GR) level (SI mitochondrial complex-I 30-kDa protein in the context of Appendix, Fig. S1F), demonstrating specificity of YME1L regu- PD (7). lation of poly(GR). Expansion of G4C2 repeats in the 5′-UTR of C9ORF72 is the We further confirmed the YME1L effect on poly(GR) in most common genetic cause of ALS with frontotemporal de- mammalian cells. Flag-GR80 accumulated to higher levels in mentia (C9-ALS/FTD). A number of mechanisms have been put YME1L knockout HEK293 cells generated by CRISPR-Cas9 forward to explain the pathogenesis of G4C2 repeat expansion (Fig. 1E), a phenotype that was rescued by WT YME1L but (19, 20), including C9ORF72 haplo-insufficiency, toxicity asso- not a catalytically inactive YME1L-E543Q (Fig. 1F). Conversely, ciated with sense and antisense RNA foci, or proteotoxicity in- overexpression YME1L-GFP or YME1L-Flag dramatically re- duced by dipeptide repeat (DPR) proteins (GA, GP, GR, PA, duced GR80 level (Fig. 1 G and H), whereas YME1L-E543Q- PR) translated from G4C2 repeat-carrying sense and antisense Flag failed to do so (Fig. 1H). In C9-ALS/FTD patient fibro- transcripts in all six possible reading frames. Increasing evidence blasts containing expanded G4C2 repeats, poly(GR) but not emphasizes the pathogenic contribution of DPRs, with arginine- poly(GA) level was reduced by YME1L cDNA and elevated by containing poly(GR) and poly(PR) exhibiting particular cyto- YME1L small-interfering RNA (siRNA) transfections (SI Ap- toxicity (19–22). Despite intensive recent efforts, how the ex- pendix, Fig. S1G). Mitochondrial defects (swelling, vacuolization, pression of the poly(GR) protein causes cellular toxicity remains and loss of cristae) seen in patient fibroblasts were also rescued unclear, and even less is known about cellular mechanisms that by YME1L-OE (SI Appendix, Fig. S1H). These results implicate protect against such toxicity. Here we report a mechanism of mitochondria as major sites of poly(GR) toxicity and YME1L, a poly(GR) toxicity that
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