RESISTANCE TO HYPOXIA IN RAINBOW TROUT: DECODING THE ROLE OF CHAPERONE-MEDIATED AUTOPHAGY

Back to jobs listing

INRAE presentation

The French National Research Institute for Agriculture, Food, and Environment (INRAE) is a major player in research and innovation. It is a community of 12,000 people with 272 research, experimental research, and support units located in 18 regional centres throughout France. Internationally, INRAE is among the top research organisations in the agricultural and food sciences, plant and animal sciences, as well as in ecology and environmental science. It is the world’s leading research organisation specialising in agriculture, food and the environment. INRAE’s goal is to be a key player in the transitions necessary to address major global challenges. Faced with a growing world population, climate change, resource scarcity, and declining biodiversity, the Institute has a major role to play in building solutions and supporting the necessary acceleration of agricultural, food and environmental transitions.

Work environment, missions and activities

OFFER DESCRIPTION

During the last 60 years, the global population has increased with an annual rate of 1.6%, and is predicted to reach 9.7 billion by 2050 according to the Food and Agriculture Organization (FAO) of the United Nations (UN)¹. Hence, providing a sustainable food supply to that exponentially growing human population is one of the core challenges of the Sustainable Development Goals of the 2030 UN Agenda. Aquaculture will definitely play an important role in fulfilling that goal. Factually, fish farming production already reached 56% of fish consumed in 2020, and still has the potential to steadily increase in the long term¹. However, despite the considerable promise of global aquaculture, the sector's sustainability hangs in the balance, as the predicted effects of climate change are not merely a future concern but an immediate reality². Aquaculture farms are thus already facing challenges such as rising water temperatures, acidification, and hypoxia, highlighting the urgent need for innovative solutions to ensure sustainable production in this changing environment. In this context, studying and harnessing the mechanisms and processes of cellular resilience, which integrate environmental stress signals and enable organisms to adapt, is of particular importance, in order to increase the robustness of fish and thus guarantee more stable and predictable production.

Among the mechanisms of cellular resilience, chaperone-mediated autophagy (CMA) attracted the attention of many scholars in recent years³. CMA is a major pathway of lysosomal proteolysis⁴. In detail, during CMA, cytosolic proteins containing a pentapeptide sequence biochemically similar to KFERQ (lysine-phenylalanine-glutamate-arginine-glutamine) are first recognized by the heat-shock protein HSC70. The substrate-chaperone complex then docks at the lysosomal membrane through specific binding to the cytosolic tail of the protein LAMP2A, the only one of the three spliced isoforms of the LAMP2 gene recognized to be essential and limiting for CMA activity. LAMP2A then organizes into a multimeric complex that allows substrates to translocate across the lysosomal membrane, where degradation by acid hydrolases occurs. Besides being involved in protein quality control(s) (resulting from its ability to selectively target damaged or non-functional proteins for degradation), the diversity of the sub-proteome degraded by CMA links this function to the regulation of a variety of intracellular processes including the control of transcription, cell cycle and cellular energetics, among other key cellular processes^{3, 4}. Recently, CMA has been recognized as a critical mechanism for cell survival under hypoxic stress in various models^5-7. While the exact mechanisms underlying this effect remain to be clarified, these findings underscore the promising potential of CMA activation as a protective strategy in low oxygen conditions.

In fish, the existence of CMA has been overlooked until recently. Indeed, the lack of any identifiable LAMP2A protein outside of the tetrapod clade led many authors to consider this function to be restricted to mammals and birds⁸. However, we recently shed new light on the evolutionary history of LAMP2A and demonstrated its expression in most of the fish investigated, suggesting that CMA likely appeared earlier during evolution than initially thought⁹. In this regard, we recently provided evidence for a functional CMA process in rainbow trout (RT, Oncorhynchus mykiss) and showed that, akin to mammals, CMA also plays a key role as a gatekeeper of cellular homeostasis in this species^{10, 11}. However, our understanding of the CMA function in RT is still fragmentary, and many questions remain unanswered, notably regarding its regulation and physiological roles in this species.

In this context, the present PhD project aims to bridge basic and translational research by investigating CMA in RT under hypoxic stress and exploring its potential to mitigate the detrimental effects of hypoxia. The expected results will deepen our understanding of CMA and determine the importance of this cellular stress response pathway in developing new farming strategies that ensure sustainable aquaculture production in the context of global changes.

References (those from the hosting lab are in bold)

1. FAO. 2024. The State of World Fisheries and Aquaculture 2024 – Blue Transformation in action. Rome.
2. Yadav et al. Climate change effects on aquaculture production and its sustainable management through climate-resilient adaptation strategies: a review. Environ Sci Pollut Res. 2024, 31, 31731–31751.
3. Valdor and Martinez-Vicente M. The Role of Chaperone-Mediated Autophagy in Tissue Homeostasis and Disease Pathogenesis. Biomedicines. 2024, 12(2):257.
4. Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol. 2018 Jun;19(6):365-381.
5. Ghosh et al. Chaperone-mediated autophagy protects cardiomyocytes against hypoxic-cell death. Am J Physiol Cell Physiol. 2022 323(5):C1555-C1575.
6. Kshitiz, et al. Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells. Cell Syst. 2022, 13(12):1048-1064.e7.
7. Dohi et al. Hypoxic stress activates chaperone-mediated autophagy and modulates neuronal cell survival. Neurochem Int. 2012, 60(4):431-42.
8. Galluzzi et al. Molecular definitions of autophagy and related processes. EMBO J. 2017, 36(13):1811-1836.
9. Lescat et al. Chaperone-Mediated Autophagy in the Light of Evolution: Insight from Fish. Mol Biol Evol. 2020, 37(10):2887-2899.
10. Vélez et al. Chaperone-mediated autophagy protects against hyperglycemic stress. Autophagy. 2024 Apr;20(4):752-768.
11. Schnebert et al. Chaperone-Mediated Autophagy in Fish: A Key Function Amid a Changing Environment. Autophagy Reports.

WORKING ENVIRONMENT

Nutrition Metabolism Aquaculture (NuMeA) INRAE-UPPA research unit is known worldwide and stands as a leading French research structure devoted to all aspects of fish nutrition and metabolism, including protein, lipid and carbohydrate metabolism, energetics, and environmental impact. Research at NuMeA is driven by the challenges posed by limited marine resources, the global expansion of aquaculture, and the ongoing effects of climate change. The unit focuses on understanding the cellular and molecular mechanisms, particularly nutrient-driven processes, that regulate key metabolic functions and growth in fish. Ultimately, the goal is to provide innovative aquaculture strategies that ensure the production of healthy, nutritious food for the global population while promoting sustainability and animal welfare.

In this context, the research initiative led by Iban Seiliez seeks to advance our understanding of the regulation of autophagy and its pivotal role in maintaining cellular metabolism and homeostasis in fish. Autophagy, a highly conserved process across evolution, acts as a key mechanism of cellular resilience, integrating environmental stress signals and enabling organisms to adapt effectively. Given the increasing environmental stresses faced by aquatic species, investigating autophagy responses is essential for identifying breeding strategies that enhance the robustness of fish and ensure more stable, predictable aquaculture production. To achieve our research objectives, we adopt a comprehensive, multifaceted approach that combines both in vivo and in vitro methodologies. This is further supported by state-of-the-art technologies such as super-resolution fluorescence imaging, CRISPR-Cas9 gene editing, siRNA-mediated gene knockdown, and advanced proteomics analyses. These cutting-edge tools allow us to investigate the intricate mechanisms of autophagy in unprecedented detail, providing valuable insights into how fish can be made more resilient to environmental stressors, ultimately contributing to the development of more sustainable and efficient aquaculture practices.

Training and skills

QUALIFICATIONS

The position requires a master degree (or equivalent) in biology, biotechnology, life sciences, or related overlapping fields.

• Mandatory qualifications:
  • Solid foundations in molecular and cellular biology
  • Good written and verbal communication skills in English and ability to work in an international environment
• Expected qualifications:
• Self-motivation, independence, and enthusiasm
• Excellent work ethic and commitment to the job
• Strong problem-solving skills and attention to detail
• Ability to work collaboratively in a multidisciplinary team

Flexibility and adaptability to changing research environments

INRAE's life quality

By joining our teams, you benefit from (depending on the type of contract and its duration):

- up to 30 days of annual leave + 15 days "Reduction of Working Time" (for a full time);
- parenting support: CESU childcare, leisure services;
- skills development systems: training, career advise;
- social support: advice and listening, social assistance and loans;
- holiday and leisure services: holiday vouchers, accommodation at preferential rates;
- sports and cultural activities;
- collective catering.

How to apply

APPLICATION 

Your application must include:

• Cover letter explaining:
• why the candidate considers oneself suitable for the position
• what motivates the candidate to apply for the position and what the candidate expects from this position
• CV
• Diploma for bachelor's and master's degree
• Transcript of grades/academic record for bachelor's and master's degree
• At least 2 references with contact information

Qualification with a master’s degree is required before commencement in the position. If you are near completion of your master’s degree, you may still apply and submit a draft version of the thesis and a statement from your supervisor or institution indicating when the degree will be obtained. You must still submit your transcript of grades for the master’s degree with your application.

 

ASSESSMENT

The applicants will be assessed by an expert committee. The committee's mandate is to undertake an assessment of the applicants' qualifications based on the written material presented by the applicants.

The applicants who are assessed as best qualified will be called to an interview. The interview should among other things, aim to clarify the applicant’s motivation and personal suitability for the position.

 

WHERE AND WHEN TO APPLY

The complete set of documents listed above must be submitted to iban.seiliez@inrae.fr by June 1st, 2025. Applications submitted after this date will not be considered. Incomplete applications will be deemed ineligible and will not be evaluated.