On 23 May at 10.15 Tiit Örd will defend his doctoral thesis titled “Functions and regulation of the mammalian pseudokinase TRIB3”.
Supervisors: TÜ MRI molekulaarbioloogia professor Jaanus Remme ja Eesti Biokeskuse vanemteadur Tõnis Örd.
Opponent: dotsent (hisp. Profesor Titular de Universidad, ingl. Associate Professor) Guillermo Velasco Diez, PhD Madridi Complutense Ülikool, Hispaania.
Summary: Tribbles homolog 3 (TRIB3) is a mammalian gene that is upregulated in response to several types of cellular stress, including glucose or amino acid deprivation, endoplasmic reticulum stress, hypoxia and oxidative stress. The TRIB3 protein is a pseudokinase, i.e., a protein that displays sequence similarity to protein kinases but contains substitutions at positions that are critical for catalytic activity in canonical protein kinases. TRIB3 is known to form protein–protein interactions with several transcription factors, protein kinases, ubiquitin ligases and other proteins, and, through these interactions, TRIB3 is implicated in the regulation of the cellular stress response, cell death, developmental processes, inflammation and metabolism. In this dissertation, several aspects of TRIB3 gene regulation and function were studied at the cell and organism levels, facilitated by the generation of a Trib3 knockout mouse line by our group. To obtain a better understanding of TRIB3 induction mechanisms, comparative quantification of different TRIB3 mRNA isoforms was performed in human hepatoma cells, revealing that mRNA isoforms containing a truncated 5′-UTR become predominant in stressful conditions, enhancing the translational potential of the TRIB3 mRNA pool. Studying the role of mouse Trib3 in mast cells, tissue-resident immune cells that mediate allergic responses, it is shown that the growth factor interleukin-3 positively regulates Trib3 expression in these cells, and a lack of Trib3 impairs the immunological functions of mast cells, implicating Trib3 in the modulation of the immune response. Analysis of Trib3 expression in the mouse brain uncovered upregulation during embryonic brain development and after the consumption of an amino acid-deficient diet. Trib3 knockout mice exhibited enlarged lateral ventricles in the brain; nevertheless, long-term spatial memory, fear memory and aversion to amino acid-imbalanced diet appear unaltered by a lack of Trib3. Finally, the role of TRIB3 in the cellular stress response to glucose deficiency was investigated using genome-wide gene expression profiling. Crucially, TRIB3 substantially alleviated the repression of IGFBP2 in glucose-deprived cells, which represents a novel mechanism of deferring cell death caused by nutrient deficiency.