Hbxip is essential for murine embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1

Abstract

Hbxip, also named Lamtor5, has been well characterized as a transcriptional coactivator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5, and that depletion of Hbxip compromises the self-renewal of embryonic stem cells (ESCs), with reduced expression of pluripotency genes, reduced cell proliferation, and decreased colony forming capacity. In addition, both Hbxip−/- ESCs and E7.5 embryos display defects in ectodermal and mesodermal differentiation. Mechanistically, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, display differentiation defects similar to those of Hbxip−/- ESCs. Moreover, Hbxip−/-, p14−/-, and p18−/- mice, lacking subunits of the Ragulator complex, also share similar phenotypes, embryonic lethality and retarded growth around E7-8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.

Research progress on oncoprotein hepatitis B X‑interacting protein (Review)

“…For example, the self-renewal and differentiation of embryonic stem cells are regulated by mTORC1 signaling. In mice, knockout of HBXIP causes mTORC1 inactivation, which further affects the differentiation of embryonic stem cells and eventually leads to embryonic lethality ( 23 ).…”

“…The carcinogenic mechanism of HBXIP in most tumors has been established, but its role in normal cells has been less well studied. At present, the role of HBXIP in maintaining normal glucose tolerance phenotype and normal embryonic tissue development in mice has been preliminarily studied ( 22 , 23 ). Likewise, HBXIP is involved in DNA damage repair ( 21 ).…”

The cellular and molecular targets of natural products against metabolic disorders: a translational approach to reach the bedside

“…CETSA and co‐immunoprecipitation revealed that nuciferine directly binds to the Ragulator subunit HBXIP) and impairs the interaction between the Ragulator complex and Rag GTPases, 126 which is crucial for the activation of mTORC1. 127 Due to its interaction with HBXIP and inhibition of mTORC1, nuciferine could activate TFEB‐mediated ALP by inhibiting TFEB phosphorylation at Ser211. Taken together, these results suggested that nuciferine may be a promising candidate for MAFLD treatment and that modulation of the mTORC1–TFEB–ALP axis represents a novel pharmacological therapy for MAFLD.…”

Defective Lamtor5 Leads to Autoimmunity by Deregulating v‐ATPase and Lysosomal Acidification

“…[ 20 ] Lamtor5 is originally recognized as an oncogenic protein with the ability to promote cellular proliferation and survival, [ 21 , 22 , 23 ] but recent data indicate that Lamor5 may have non‐carcinogenic roles such as the immunoregulatory function. [ 24 ] Global deletion of Lamtor5 caused embryonic lethality in mice, [ 25 ] implying a crucial and non‐redundant role for this molecule, of which we know little. Another critical but poorly understood question is whether the Ragulator component like Lamtor5 would interact with v‐ATPase and/or Rag GTPase to modulate mTORC1 activity.…”