Biology subjects

Gazit, R.

Publications and source records attributed to Gazit, R..

3 recordsLinked to original sources

bioRxiv2023

Acetylation-dependent coupling between G6PD activity and apoptotic signaling

Lysine acetylation has been discovered in thousands of non-histone human proteins, including most metabolic enzymes. Deciphering the functions of acetylation is key to understanding how metabolic cues mediate metabolic enzyme regulation and cellular signaling. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is acetylated on multiple lysine residues. Using site-specifically acetylated G6PD, we show that acetylation can activate (AcK89) and inhibit (AcK403) G6PD. Acetylation-dependent inactivation is explained by structural studies showing distortion of the dimeric structure and active site of G6PD. We provide evidence for acetylation-dependent K95/97 ubiquitylation of G6PD and Y503 phosphorylation, as well as interaction with p53 and induction of early apoptotic events. Notably, we found that the acetylation of a single lysine residue coordinates diverse acetylation-dependent processes. Our data provide an example of the complex roles of acetylation as a posttranslational modification that orchestrates the regulation of enzymatic activity, posttranslational modifications, and apoptotic signaling

biochemistry↗

bioRxiv2022

Rapid Activation of Hematopoietic Stem Cells

Adult Hematopoietic Stem Cells (HSCs) in the bone marrow (BM) are quiescent. Following perturbations, such as blood loss or infection, HSCs may undergo activation to accelerate the production of needed effector blood and immune cells. Surprisingly, little is known about the earliest stages of HSC activation. We utilize surface markers of HSC activation, CD69, and CD317, revealing response as early as 2 h after stimulation. The dynamic expression of HSC activation markers varies between viral-like (poly-Inosinic-poly-Cytidylic) or bacterial-like (Lipopolysaccharide) immune stimuli. We further quantify the dose response, demonstrating a low-threshold and similar sensitivity of HSCs and progenitors in the BM. Finally, we find a positive correlation between the expression of surface activation markers and early exit from quiescence into proliferation. Our data show that the premier response of adult stem cells to immune stimulation is rapid, sensitive, and directly leads to proliferation.

immunology↗

bioRxiv2020

Tumor-educated uncommitted hematopoietic stem cells promote a metastatic switch

Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, little is known about their education and differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) during tumor progression and metastasis. Here we show that metastatic tumors dictate a unique differentiation pattern of HSPCs towards a specific myeloid progeny. Using single cell RNA-sequencing analysis integrated with proteomic screen of tumor secretome, we demonstrate that highly metastatic tumors dictate a long-lived differentiation of HSPCs towards monocyte-dendritic progenitors (MDPs) while low-metastatic tumors promote their differentiation into granulocyte-monocyte progenitors (GMPs). This effect is driven by IL-6 axis that is highly active in metastatic tumors. Consequently, loss and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Consistently, IL-6-educated MDPs but not GMPs obtained from highly metastatic tumors, adoptively transferred into mice bearing low metastatic tumors resulted in increased metastasis due to their further differentiation into immunosuppressive (M2) macrophages. Overall, our study reveals a new role for tumor-derived IL-6 that hijacks HSPC differentiation program towards myeloid cells that contribute to metastasis.

cancer biology↗