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Unraveling the mechanism by which Rps26-deficient ribosomes form to support the stress response

Award Number: F32GM139302
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2022

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Unraveling the mechanism by which Rps26-deficient ribosomes form to support the stress response - Project Summary/Abstract Recently ribosome subpopulations that differ in their composition, lacking individual ribosomal proteins (RPs), or containing specific modifications have garnered a lot of interest. In the case of RP content, multiple studies have shown that ribosomes lacking specific RPs are present in cells, including ribosomes deficient in Rps26. While their physiological relevance remains unclear in most cases, the Karbstein lab has recently demonstrated that ribosomes lacking Rps26 are produced specifically under high salt and pH stress to enable the preferential translation of mRNAs encoding proteins from the Hog1 and Rim101 pathways that are required for the response to these stresses. This change in mRNA specificity between Rps26-containing and deficient ribosomes arises from the recognition of the -4 position of the Kozak sequence by Rps26, thereby supporting the translation of well-translated mRNAs by Rps26-containing ribosomes in rich medium, and the translation of specific mRNAs in the Hog1 and Rim101 pathways by Rps26-deficient ribosomes that are formed under these stresses. What remains unknown is how Rps26-deficient ribosomes form under high salt and high pH stress. My preliminary results suggest Rps26-deficient ribosomes are produced by release of Rps26 from pre-existing ribosomes. Therefore, I will further dissect in more detail the mechanism that leads to the production of Rps26- deficient ribosomes, exploring the role of the Rps26-specific chaperone Tsr2 in delivering to and extracting Rps26 from ribosomes (Aim1), and testing which posttranslational modifications regulate this pathway (Aim2). Next, I will test if Rps26 is (re-) incorporated into Rps26-deficient ribosomes, to allow for a rapid switch in mRNA-specificity without the costs of re-building new ribosomes, or whether instead these ribosomes are degraded (Aim3). Together, these experiments will clarify how Rps26-deficient ribosomes form under stress. In addition to further expanding on this novel paradigm of stress-induced production of a specific ribosome population, the results will also have implications for the development of diseases linked to Rps26-deficiency, such as Diamond- Blackfan anemia. Because the etiology of 10-15% of all cases remains unknown, and is not linked to RP- deficiency, it is possible that overactivation of pathways leading to the release of RPs such as Rps26 might be responsible for a subset of cases, similar to the subset of cases caused by deficiency of the Rps26-chaperone Tsr2. Furthermore, ribosomes lacking individual RPs, including Rps26, are produced in cancer cells, where they are associated with poor outcomes. Thus, this work will also help delineate how cancer cells modulate the translational machinery to subvert translation to its purposes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$7,837 )
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	5/15/2023	NON-COMPETING CONTINUATION	-$5,787
2023	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	3	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$2,050
														Subtotal = -$7,837

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	5/3/2022	NON-COMPETING CONTINUATION	-$18,491
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	3	5/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$18,491
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $68,562 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	6/30/2021	NON-COMPETING CONTINUATION	$68,562
														Subtotal = $68,562

Issue Date FY: 2020 ( Subtotal = $65,310 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	1	6/18/2020	NEW	$65,310
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	001	1	6/25/2020	NEW	$0
														Subtotal = $65,310

Grand Total All Awards = $126,035

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Unraveling the mechanism by which Rps26-deficient ribosomes form to support the stress response

Award Number: F32GM139302

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2022

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