RETRACTED: Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks
Authors: Ania Busza
Jinli Ling
Xiaohu Zhao
Patrick Emery
Ozgur Tataroglu
John S O&#x27;Neill
Journal: Cell (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Circadian clocks; temperature; light input; molecular mechanisms; Drosophila

Abstract:  Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles. 

Retracted: Yes

PubPeer comments:
 http: dx.doi.org 10.1016 j.cell.2017.09.013 This article has been retracted at the request of the authors editors. In the above article, we presented evidence that temperature phase shifts animal circadian clocks through regulated degradation of critical circadian pacemaker proteins mediated by calcium and SOL protease. In follow-up experiments, other members of the corresponding authoru2019s laboratory were unable to reproduce key observations made in vivo that supported the role of calcium and SOL protease in signaling temperature input to the Drosophila circadian clock. An in-depth review of the dataset generated by the first author revealed clear evidence that he had repeatedly misrepresented and altered primary data pertaining to the role of calcium, calmodulin, and SOL protease in Drosophila during the study. An independent investigation conducted by the University of Massachusetts Medical School concluded that the first author committed scientific misconduct. Since the manipulated datau2014which measured the amplitude of circadian phase shifts in response to temperature pulses in various genotypes using luciferase and behavioral assaysu2014were critical to support our conclusions, we are retracting the above article. We sincerely apologize to the scientific community for publishing this erroneous article and profoundly regret any inconvenience and confusion that it might have caused. The first author, Ozgur Tataroglu, declined to sign this retraction. , 
 ORI Case https: ori.hhs.gov content case-summary-tataroglu-ozgur? **Case Summary: Tataroglu, Ozgur** Ozgur Tataroglu, Ph.D., University of Massachusetts Medical School: Based on the report of an investigation conducted by the University of Massachusetts Medical School (UMMS) and additional analysis conducted by the Office of Research Integrity (ORI) in its oversight review, ORI found that Dr. Ozgur Tataroglu, former postdoctoral fellow, Department of Neurobiology, UMMS, engaged in research misconduct in research supported by U.S. Public Health Service (PHS) funds, specifically National Institute of General Medical Sciences (NIGMS), National Institutes of Health (NIH), grants R01 GM066777 and R01 GM079182. Respondent neither admits nor denies ORIu2019s findings of research misconduct. The settlement is not an admission of liability on the part of the Respondent. The parties entered into a Voluntary Settlement Agreement (Agreement) to conclude this matter without further expenditure of time, finances, or other resources. ORI found that Respondent engaged in research misconduct by knowingly, intentionally, and or recklessly falsifying data included in the following one (1) paper and two (2) grant applications submitted to NIGMS, NIH: Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks. Cell 2015 Nov 19;163(5):1214-1224 (hereafter referred to as u201cCell 2015u201d). Retracted in: Cell 2017 Sep 21;171(1):256. R01 GM079182-05A1, u201cSynchronization of Drosophila Circadian Rhythms by Temperature Cycles,u201d submitted to NIGMS, NIH, on July 18, 2014. R35 GM118087-01, u201cMolecular and neural mechanisms generating and synchronizing circadian rhythms,u201d submitted to NIGMS, NIH, on May 19, 2015. Specifically, ORI found that Respondent engaged in research misconduct by knowingly, intentionally, and or recklessly falsifying data in bar graphs representing phase shift of circadian clock activity between Drosophila without and with heat pulse (HP) treatment in: Figures 1G, 2F, 3C, and 4C of Cell 2015; Figures 7D, 8G, and 9C in grant application R01 GM079182-05A1; Figures 3C and 4 in grant application R35 GM118087-01; and two (2) figures recorded in his unpublished data files, by selectively altering the original Drosophila behavior locomotor data in his primary data files. The data manipulations resulted in the creation or exaggeration of phase shifts caused by either HP treatment or over-expression of the calpain protease SOL, to support the hypothesis that temperature phase shifts the Drosophila circadian clock through the regulated degradation of the pacemaker protein TIMELESS mediated by SOL. Dr. Tataroglu entered into an Agreement and voluntarily agreed: to have his research supervised for a period of three (3) years beginning on December 30, 2019; Respondent agreed that prior to the submission of an application for PHS support for a research project on which Respondentu2019s participation is proposed and prior to Respondentu2019s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondentu2019s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondentu2019s research contribution; Respondent agreed that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agreed to maintain responsibility for compliance with the agreed supervision plan; that the requirements for Respondentu2019s supervision plan are as follows: a committee of 2-3 senior faculty members at the institution who are familiar with Respondentu2019s field of research, but not including Respondentu2019s supervisor or collaborators, will provide oversight and guidance for three (3) years beginning on December 30, 2019; the committee will review primary data from Respondentu2019s laboratory on a quarterly basis and submit a report to ORI at six (6) month intervals setting forth the committee meeting dates, Respondentu2019s compliance with appropriate research standards, and confirming the integrity of Respondentu2019s research; and the committee will conduct an advance review of any PHS grant applications (including supplements, resubmissions, etc.), manuscripts reporting PHS-funded research submitted for publication, and abstracts; the review will include a discussion with Respondent of the primary data represented in those documents and will include a certification to ORI that the data presented in the proposed application publication is supported by the research record; that for a period of three (3) years beginning on December 30, 2019, any institution employing him shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; that if no supervisory plan is provided to ORI, Respondent shall provide certification to ORI at the conclusion of the supervision period that he has not engaged in, applied for, or had his name included on any application, proposal, or other request for PHS funds without prior notification to ORI; and to exclude himself voluntarily from serving in any advisory capacity to PHS including, but not limited to, service on any PHS advisory committee, board, and or peer review committee, or as a consultant for a period of three (3) years beginning on December 30, 2019. ,