Transglutaminase Type 2 is Involved in the Hematopoietic Stem Cells Homeostasis

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S. Oliverio^1#, J. S. O. Beltran^1,2#, L. Occhigrossi¹, V. Bordoni³, C. Agrati³, M. D’Eletto¹, F. Rossin¹, P. Borelli², G. P. Amarante-Mendes⁴, O. Demidov⁵, N. A. Barlev⁵, and M. Piacentini^1,3,5,a*

¹Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy

²Clinical and Experimental Hematology Laboratory, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil

³National Institute for Infectious Diseases I. R. C. C. S. “Lazzaro Spallanzani” 00149 Rome, Italy

⁴Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

⁵Laboratory of Molecular Medicine, Institute of Cytology, Russian Academy of Sciences, 194064 St.-Petersburg, Russia

^# These authors contributed equally to this work.

^* To whom correspondence should be addressed.

Received July 9, 2020; Revised July 21, 2020; Accepted July 21, 2020

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Type 2 transglutaminase (TG2) is a multifunctional protein involved in various biological processes playing a key regulatory role in cell homeostasis such as cell death and autophagy. New evidence is emerging that support an important role of autophagy in regulating normal hematopoiesis. Prompted by these findings, in this study we investigated in vivo involvement of TG2 in mouse hematopoiesis under normal or nutrient deprivation conditions. We found that the number and rate of differentiation of bone marrow hematopoietic stem cell was decreased in the TG2 knockout mice. We present evidence showing that these effects on hematopoietic system are very likely due to the TG2-dependent impairment of autophagy. In fact, stimulation of autophagy by starvation is able to rescue the block of the differentiation of stem cells progenitors in the TG2 KO mice. It was also shown that the RhoA/ERK½ pathway, known to be essential for regulation of the bone marrow progenitor cells homeostasis, was significantly impaired in the absence of TG2. Hence, this study expanded our knowledge about TG2 discovering a role of this enzyme in regulation of hematopoiesis.

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KEY WORDS: TG2, hematopoietic stem cells, autophagy

DOI: 10.1134/S0006297920100041

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