Taspase1 orchestrates fetal liver hematopoietic stem cell and vertebrae fates through cleaving TFIIA

Abstract

Taspase1, a highly conserved threonine protease encoded by TASP1, cleaves nuclear histone modifying factors and basal transcription regulators to orchestrate diverse transcription programs. Hereditary loss-of-function mutation of TASP1 has recently been reported in human resulting in a novel anomaly complex syndrome manifested with hematological, facial, and skeletal abnormalities. Here, we demonstrate that Taspase1mediated cleavage of TFIIAa-b, rather than of MLL1 or MLL2, in mouse embryos is required for proper fetal liver hematopoiesis and correct segmental identities of the axial skeleton. Homozygous genetic deletion of Taspase1 (Tasp1 -/-) disrupted embryonic hematopoietic stem cell self-renewal and quiescence states, and axial skeleton fates. Strikingly, mice carrying knockin non-cleavable mutations of TFIIAa-b (Gtf2a1 nc/nc ), a well-characterized basal transcription factor, displayed more pronounced fetal liver and axial skeleton defects than those with non-cleavable MLL1 and MLL2 (Mll1 nc/nc ;2 nc/nc ), two trithorax group (Trx-G) histone H3 trimethyl transferases. Our study offers molecular insights concerning TASP1-loss human syndrome and discovers unexpected role of TFIIAa-b cleavage in embryonic cell fate decisions.

The Taspase1/Myosin1f-axis regulates filopodia dynamics

“…A comparable clinic-pathologic pattern was observed for Tasp1 deficient mice. Besides massive early postnatal lethality, Tasp1 À/À animals are smaller in size and display profound skeletal abnormalities coupled with an impaired cell proliferation and a decrease in thymocytes and hematopoietic stem cells (Takeda et al, 2006;Niizuma et al, 2015Niizuma et al, , 2021. Those observations are consistent with the results of our study, as we provide first evidence that Tasp1 activity might play a role in developmental processes of immune cells.…”

Structural and functional diversity of asparaginases: Overview and recommendations for a revised nomenclature

“…For example, some hydrolyze dipeptides of β aspartyl and function in the metabolism of oligosaccharides or are Thr endopeptidase 30,31 . In this context, it is important to note that all the enzymes present K M for l ‐Asn in the mM range 31–33 . Class 2 ASNases also retain high conservation in secondary protein folding (Fig.…”

“…2(A)). 30,33 The human isoform of Thr aspartase 1 (Fig. 2(G), Taspase1) is composed of 420 amino acids and has a molecular mass of 45 kDa.…”

Closantel is an Allosteric Inhibitor of Human Taspase1

“…Besides its role in the functional processing of MLL protein, Taspase1 also plays an important role in TFIIA processing (Zhou et al, 2006;Malecova ´et al, 2015), and this function appears to be quite important for fetal hematopoiesis and proper facial and axial skeleton development (Niizuma et al, 2021). In particular, cranial development and craniofacial anomalies have been linked to a specific V343M mutation in Taspase1 (Takeda et al, 2015;Balkin et al, 2019).…”