NUFIP1 is a ribosome receptor for starvation-induced ribophagy
Authors: Caroline A Lewis
Nouf N Laqtom
Sze Ham Chan
Monther Abu-Remaileh
Ivonne Heinze
Vimisha Dharamdasani
Alessandro Ori
Evgeni M Frenkel
Gregory A Wyant
David M Sabatini
Journal: Science (2018)
Discipline: Multidisciplinary
Keywords: lysosome; proteomic analysis; mTORC1; NUFIP1; autophagosomes
Affiliations: Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA., Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA., Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany., Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany.  ., Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.  .

Abstract:  The lysosome degrades and recycles macromolecules, signals to the master growth regulator mTORC1 [mechanistic target of rapamycin (mTOR) complex 1], and is associated with human disease. We performed quantitative proteomic analyses of rapidly isolated lysosomes and found that nutrient levels and mTOR dynamically modulate the lysosomal proteome. Upon mTORC1 inhibition, NUFIP1 (nuclear fragile X mental retardation-interacting protein 1) redistributes from the nucleus to autophagosomes and lysosomes. Upon these conditions, NUFIP1 interacts with ribosomes and delivers them to autophagosomes by directly binding to microtubule-associated proteins 1A/1B light chain 3B (LC3B). The starvation-induced degradation of ribosomes via autophagy (ribophagy) depends on the capacity of NUFIP1 to bind LC3B and promotes cell survival. We propose that NUFIP1 is a receptor for the selective autophagy of ribosomes. 

Retracted: No

PubPeer comments:
 Readers should become aware of a recent paper published Nature that calls into question part of the conclusions by Wyant et al., 2018, entitled Systematic quantitative analysis of ribosome inventory during nutrient stress https: www.nature.com articles s41586-020-2446-y From the Results section: NUFIP1u2014a subunit of the nucleoplasmic R2TP pathway that is involved in 60S rRNA biogenesis2u2014was reported to traffic to the cytosol in response to nutrient stress and to function as a selective ribophagy receptor for lysosomal delivery4,22. **The absence of NUFIP1 re-localization after amino acid withdrawal (as measured by TMT-based proteomics; Extended Data Fig. 7j, k) led us to re-evaluate its role in ribophagy. First, NUFIP1u2212 u2212 293T cells exhibit reduced levels of r-proteins in rich medium, in line with the previously defined role of R2TP in 60S biogenesis (Extended Data Fig. 9a, b). Second, NUFIP1 deletion had no effect on the total Ribou2013Halo abundance, synthesis or dilution (Extended Data Fig. 9cu2013e), or on r-protein abundance as measured by TMT-based proteomics (Extended Data Fig. 9fu2013i) during mTOR inhibition. Third, RPS3u2013Keima flux was unaffected in NUFIP1u2212 u2212 cells subjected to nutrient stress (Extended Data Fig. 9j). We conclude that NUFIP1 is not required for ribophagic flux in these stress conditions** , 
 To give some background on the story, the initial paper by Heeseon An and Wade Harper published in Nature Cell Biology, before Sabatini s paper, already contradicted the notion of selective ribophagy https: www.nature.com articles s41556-017-0007-x Following the publication of Wyant s Abu-Remaileh paper, Harper and Heeseon published a nice review articulating the conflicting data, ultimately casting doubt on the results. However, it was not until the publication of their Nature paper in 2020 that they were able to substantiate their argument with data finally disproving the paper from Wyant, Abu-Remaileh and Sabatini. , 
 I think it would be desirable for the authors to respond to these serious allegations in this Nature paper - especially given the potential impact on the work of other scientists working in the field of ribophagy. Certainly, it would be good practice to respond either through this platform or through the journals involved - ideally with the help of additional experiments to support the claims of the Science paper. The very fact that NUFIP1 was selected from the proteomic interaction data in Sabatini s Science paper is remarkable: in Supplementary Table 1 (proteomic IP data), this protein is found at position 4323: log2FC: -0.3; Q-value: 0.212. Perhaps the authors could explain the scientific rationale for selecting NUFIP1 as a hit from this list? In the Science paper they simply write:  (NUFIP1) piqued our interest because previous work indicates that while NUFIP1 is largely a nuclear protein it has also been observed in the cytoplasm of some cell types . However, this is certainly also true for the ~4000 protein, which would be far better candidates than NUFIP1. I think the scientific community would be very interested to know which of these contradictory findings is ultimately correct. , 
 The Western blot assembly of Fig. 6a is somewhat curious. The images contained in the PDF show that rows 2-6 (RPL7 to Golgin-97) consist of 5 columns with signal that are flanked by an empty column. In the PDF assembly the left four columns are used. Row 1 (RPS15A) is assembled differently. It too consists of 5 columns with signal, but the cut is very different. Also, this time the right 4 columns are used. Did the WBs all originate from the same gel? ![file] ,