Poster abstracts
Poster number 174 submitted by Aleksandr Ivanov
Deciphering function and mechanism of translation elongation factor eIF5A in heart
Aleksandr Ivanov (Aab Cardiovascular Institute, School of Medicine and Dentistry, University of Rochester), Jiali He (Aab Cardiovascular Institute, School of Medicine and Dentistry, University of Rochester), Yui Kawakami (Aab Cardiovascular Institute, School of Medicine and Dentistry, University of Rochester), Peng Yao (Aab Cardiovascular Institute, School of Medicine and Dentistry, University of Rochester)
Abstract:
Translation elongation is a key step in protein synthesis for proteostasis. However, the ribosome slows and stalls at poly-proline codons during elongation, leading to disrupted proteostasis and cellular function. An elongation factor eIF5A facilitates the translation of such codons and helps ribosomes avoid stalling. Prior studies have shown a connection between eIF5A dysfunction and heart disease. Deficiency of eIF5A in the heart is associated with pathological conditions. Slow translation elongation in CM poses a higher risk of ribosomal stalling; therefore, CM has evolved a specialized RPL3L-containing ribosome to efficiently read through proline-rich codons and prevent ribosomal pausing. Human RPL3L mutations lead to infantile cardiomyopathy and heart failure. RPL3L-bearing ribosomes could serve as a backup system for CM with reduced eIF5A levels. Our recent studies have demonstrated that a mouse model with conditional knockout (cKO) of Eif5a in CM exhibiting cardiac remodeling and heart failure accompanied by morphological, histological, echocardiographic, and molecular changes. Combining multiomics approaches, we identified a set of eIF5A-regulated mRNAs with defective elongation through stalling sites. Besides direct effect in CM, we found translation repression of proline-rich protein in cardiac fibroblasts (CF), likely caused by intercellular communications between CM and CF. However, cKO of eIF5A in CF mouse model did not cause heart failure. On the contrary, it mitigated heart failure under angiotensin II neurohumoral stress. One major change we discovered in Eif5a cKO hearts was an increase in RPL3L mRNA & protein accompanied by a decrease in its paralog protein RPL3 two weeks after cKO. I performed lentiviral shRNA knockdown of eIF5A and its modifying enzyme DOHH in human AC16 CM cells to confirm findings in mice. Consistently, the increase in RPL3L progressed upon eIF5A or DOHH knockdown in a time-dependent manner.
Keywords: eIF5A, RPL3L, cardiovascular