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Spoon-Feeding Ribosomes to Autophagy

2018; Elsevier BV; Volume: 71; Issue: 2 Linguagem: Inglês

10.1016/j.molcel.2018.07.003

1097-4164

Hitoshi Nakatogawa,

Genetics and Neurodevelopmental Disorders

The ribosome, a ribonucleoprotein machine for protein synthesis, can also serve as an abundant nutrient source under starvation conditions. In a recent issue of Science, Wyant et al., 2018Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google Scholar discovered a specialized "spoon" to "scoop up" more ribosomes for degradation by autophagy. The ribosome, a ribonucleoprotein machine for protein synthesis, can also serve as an abundant nutrient source under starvation conditions. In a recent issue of Science, Wyant et al., 2018Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google Scholar discovered a specialized "spoon" to "scoop up" more ribosomes for degradation by autophagy. In autophagy, a small, flattened membrane vesicle forms in the cytoplasm, which expands, becomes spherical, and closes to complete a double-membrane vesicle called the autophagosome (Ohsumi, 2014Ohsumi Y. Historical landmarks of autophagy research.Cell Res. 2014; 24: 9-23Crossref PubMed Scopus (648) Google Scholar, Yang and Klionsky, 2010Yang Z. Klionsky D.J. Eaten alive: a history of macroautophagy.Nat. Cell Biol. 2010; 12: 814-822Crossref PubMed Scopus (1636) Google Scholar). In this process, different cytoplasmic molecules and their assemblies, including organelles, are sequestered into the autophagosome, which delivers the sequestered material to the lysosome or vacuole for degradation. Autophagic sequestration was once thought to be a non-selective process, but recent studies have revealed that a wide spectrum of molecules and structures, including aberrant proteins and damaged mitochondria, are enclosed in the autophagosome in a selective manner (Stolz et al., 2014Stolz A. Ernst A. Dikic I. Cargo recognition and trafficking in selective autophagy.Nat. Cell Biol. 2014; 16: 495-501Crossref PubMed Scopus (817) Google Scholar). Non-selective autophagy is strongly induced by nutrient limitation and supplies degradation products as nutrients for cell adaption to starvation conditions. Ribosomes, one of the most abundant cytoplasmic constituents, are composed of proteins and RNAs and are likely to be a major nutrient source in this recycling process. Indeed, in an early study of yeast autophagy, electron microscopy demonstrated that autophagosomes contained lots of ribosomes as densely as those in the cytoplasm (Takeshige et al., 1992Takeshige K. Baba M. Tsuboi S. Noda T. Ohsumi Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction.J. Cell Biol. 1992; 119: 301-311Crossref PubMed Scopus (955) Google Scholar). This observation suggested that ribosomes are taken up into the autophagosome as part of the cytoplasm (Figure 1, "non-selective"). However, Kraft et al., 2008Kraft C. Deplazes A. Sohrmann M. Peter M. Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease.Nat. Cell Biol. 2008; 10: 602-610Crossref PubMed Scopus (551) Google Scholar showed that autophagy degrades ribosomes more efficiently than other cytoplasmic proteins in yeast cells starved for nitrogen. Accordingly, the term "ribophagy" was coined for selective autophagy of ribosomes. Yet, key questions remain unanswered. How are ribosomes efficiently degraded by autophagy? It is unknown even whether ribosomes are concentrated during autophagic sequestration. If so, what is the mechanism? Given that a ribophagy-specific factor had not been identified, examination of its physiological importance was difficult. It also remained to be investigated whether the ribophagy pathway exists in mammalian cells. A recent study by Wyant et al., 2018Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google Scholar has given us the answers to these questions. Mammalian target of rapamycin complex 1 (mTORC1) is the master regulator in nutrient sensing and cell growth, and its activity and lysosomal functions are closely related to each other (Saxton and Sabatini, 2017Saxton R.A. Sabatini D.M. mTOR signaling in growth, metabolism, and disease.Cell. 2017; 168: 960-976Abstract Full Text Full Text PDF PubMed Scopus (3117) Google Scholar). Autophagy is also under the control of mTORC1, whose inactivation upon nutrient deprivation leads to the induction of autophagy, which transports various molecules to the lysosome. To understand how the lysosomal proteome changes in response to mTORC1 inactivation, Wyant et al., 2018Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google Scholar performed the proteomic analysis of isolated lysosomes and identified nuclear fragile X mental retardation-interacting protein 1 (NUFIP1) as a protein whose lysosomal abundance increased upon cell treatment with the mTORC1 inhibitor Torin1. NUFIP1 was previously described as a nuclear protein that forms a complex with zinc finger HIT domain-containing protein 3 (ZNHIT3) and functions in the assembly of the box C/D small nucleolar ribonucleoprotein (snoRNP). Wyant et al., 2018Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google Scholar showed that NUFIP1 translocates from the nucleus to lysosomes when mTORC1 is inactivated. This lysosomal localization of NUFIP1 depended on ATG7, an autophagy-related protein required for autophagosome formation. Knockout of ATG7 resulted in a dispersed cytoplasmic localization of NUFIP1 in response to Torin1, suggesting a two-step process in which NUFIP1 is first exported from the nucleus to the cytoplasm and then transported to lysosomes via autophagosomes. An increasing number of examples have established that target recognition in selective autophagy is mediated by a uniform mechanism. Proteins called "autophagy receptors" bind to both degradation targets and Atg8 family proteins (LC3s and GABARAPs in mammals) on forming autophagosomal membranes, linking the targets to the membranes (Birgisdottir et al., 2013Birgisdottir Å.B. Lamark T. Johansen T. The LIR motif - crucial for selective autophagy.J. Cell Sci. 2013; 126: 3237-3247Crossref PubMed Scopus (564) Google Scholar). Autophagy receptors share an amino acid sequence motif called the Atg8-family-interacting motif or the LC3-interacting region (LIR) motif (typically, Trp/Phe/Tyr-X-X-Ile/Leu/Val) to bind Atg8 family proteins. Wyant et al., 2018Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google Scholar found that NUFIP1 interacts with LC3 via an LIR motif (Trp40-Ala-Met-Leu), raising the possibility that NUFIP1 serves as an autophagy receptor in the cytoplasm under starvation conditions. They hypothesized that the target of NUFIP1 is the ribosome, given that NUFIP1 is involved in the modification of ribosomal RNA. Indeed, they revealed that NUFIP1 associates with the large subunit of the ribosome and directs the ribosome to autophagic degradation upon mTORC1 inactivation. Importantly, the LIR motif mutant of NUFIP1, which was normal for its function in snoRNP assembly, was defective in autophagic degradation of ribosomes, a strong piece of evidence that NUFIP1 acts as an autophagy receptor for ribosomes (Figure 1, "selective"). The LIR motif mutant, which is likely to be specifically defective in ribophagy, also allowed them to examine the physiological significance of ribophagy in mammalian cells. Using this mutant, they showed that ribophagy is actually important for cells to survive nutrient starvation. They also found that the addition of nucleosides to media could support viability of ribophagy-deficient cells under starvation conditions. This seems reasonable considering that ribophagy should yield enormous amounts of nucleosides as a consequence of ribosomal RNA degradation. However, further analysis is required to conclude that externally added nucleosides actually support cell viability by compensating nucleosides that should have been supplied by ribophagy. Ribosome degradation should also generate large amounts of amino acids. NUFIP1-mediated ribophagy was shown to be important for the reactivation of mTORC1 after prolonged starvation, probably via supplying amino acids. It is uninvestigated but possible that ribophagy plays a vital role in amino acid metabolism under nutrient-limiting conditions. In this way, Wyant et al., 2018Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google Scholar revealed that mammalian cells efficiently "eat" ribosomes using a special tool when they are starved. Identification of NUFIP1 has provided the basic mechanism of ribosome sequestration in ribophagy; the interaction of NUFIP1-bound ribosomes with LC3 can increase the localized cytoplasmic ribosome concentration for sequestration into the autophagosome (Figure 1). Nonetheless, their electron microscopic analysis raises another intriguing issue. While autophagosomes in control cells contained ribosomes as dense as the cytoplasm, in the absence of NUFIP1, the ribosome density was much less in autophagosomes than that in the cytoplasm. Consistent with this observation, ribosome degradation as assessed by immunoblotting of ribosomal proteins was almost completely blocked in NUFIP1 mutant cells, even though non-selective autophagy occurs in these cells. Thus, ribosomes appear to be excluded from autophagic sequestration in NUFIP1 mutants. This suggests that, unlike our current view, ribosomes may not be taken up into the autophagosome as easily as other cytoplasmic components without help of NUFIP1. Regarding the mode of ribosome sequestration into the autophagosome, An and Harper, 2018An H. Harper J.W. Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy.Nat. Cell Biol. 2018; 20: 135-143Crossref PubMed Scopus (96) Google Scholar reported that autophagic degradation of ribosomes (as well as that of another cytosolic protein) was stimulated under conditions in which selective autophagy of organelles such as mitochondria was promoted. Based on these results, they described that ribosomes were degraded via autophagy in a "bystander" manner (Figure 1). Thus, ribosomes are scooped into the autophagosome in at least three different ways. These modes of ribosome autophagy may differently contribute to cellular homeostasis depending on intracellular environments and cell types. In some cases, recycling other essential materials in ribosomes can be important. For instance, a recent study suggested that autophagic degradation of ribosomes supports the growth of yeast under zinc deprivation by releasing the zinc used in ribosomes (Kawamata et al., 2017Kawamata T. Horie T. Matsunami M. Sasaki M. Ohsumi Y. Zinc starvation induces autophagy in yeast.J. Biol. Chem. 2017; 292: 8520-8530Crossref PubMed Scopus (45) Google Scholar). Future studies will reveal that autophagic degradation of ribosomes has a much more global impact on cellular metabolism beyond our current expectation.