bims-tunefa Biomed News
on Tumor necrosis factor superfamily and post-translational modifications
Issue of 2020‒09‒20
six papers selected by
John Silke
Walter and Eliza Hall Institute of Medical Research


  1. Semin Cell Dev Biol. 2020 Sep 13. pii: S1084-9521(20)30114-2. [Epub ahead of print]
    Liu L, Lalaoui N.
      Receptor Interacting Protein Kinase 1 (RIPK1) is a key regulator of inflammation. To warrant cell survival and appropriate immune responses, RIPK1 is post-translationally regulated by ubiquitylations, phosphorylations and caspase-8-mediated cleavage. Dysregulations of these post-translational modifications switch on the pro-death function of RIPK1 and can cause inflammatory diseases in humans. Conversely, activation of RIPK1 cytotoxicity can be advantageous for cancer treatment. Small molecules targeting RIPK1 are under development for the treatment of cancer, inflammatory and neurogenerative disorders. We will discuss the molecular mechanisms controlling the functions of RIPK1, its pathologic role in humans and the therapeutic opportunities in targeting RIPK1, specifically in the context of inflammatory diseases and cancers.
    Keywords:  Apoptosis; Cancer; Inflammation; Necroptosis; PRR; RIPK1; TNF
    DOI:  https://doi.org/10.1016/j.semcdb.2020.08.007
  2. Mol Cell Oncol. 2020 ;7(5): 1776085
    Wu W, Stork B.
      Receptor interacting serine/threonine kinase 1 (RIPK1) is the central mediator of tumor necrosis factor (TNF) signaling. It regulates both pro-survival/pro-inflammatory and cell death pathways. In order to fulfill this complex regulation, RIPK1 is regulated by several post-translational modifications, including ubiquitination, acetylation, and phosphorylation. In our recent work, we show that the unc-51-like autophagy activating kinase 1 (ULK1) phosphorylates RIPK1 at Ser357 and thus blocks TNF-induced cell death.
    Keywords:  Autophagy; RIPK1; TNF; Ulk1; necroptosis
    DOI:  https://doi.org/10.1080/23723556.2020.1776085
  3. Sci Adv. 2020 Sep;pii: eabc0418. [Epub ahead of print]6(38):
    Chatrin C, Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sumpton D, Sibbet GJ, Smith BO, Huang DT.
      Cellular cross-talk between ubiquitination and other posttranslational modifications contributes to the regulation of numerous processes. One example is ADP-ribosylation of the carboxyl terminus of ubiquitin by the E3 DTX3L/ADP-ribosyltransferase PARP9 heterodimer, but the mechanism remains elusive. Here, we show that independently of PARP9, the conserved carboxyl-terminal RING and DTC (Deltex carboxyl-terminal) domains of DTX3L and other human Deltex proteins (DTX1 to DTX4) catalyze ADP-ribosylation of ubiquitin's Gly76 Structural studies reveal a hitherto unknown function of the DTC domain in binding NAD+ Deltex RING domain recruits E2 thioesterified with ubiquitin and juxtaposes it with NAD+ bound to the DTC domain to facilitate ADP-ribosylation of ubiquitin. This ubiquitin modification prevents its activation but is reversed by the linkage nonspecific deubiquitinases. Our study provides mechanistic insights into ADP-ribosylation of ubiquitin by Deltex E3s and will enable future studies directed at understanding the increasingly complex network of ubiquitin cross-talk.
    DOI:  https://doi.org/10.1126/sciadv.abc0418
  4. Sci Adv. 2020 Aug;pii: eabc0629. [Epub ahead of print]6(34):
    Ahmed SF, Buetow L, Gabrielsen M, Lilla S, Chatrin C, Sibbet GJ, Zanivan S, Huang DT.
      Cross-talk between ubiquitination and ADP-ribosylation regulates spatiotemporal recruitment of key players in many signaling pathways. The DELTEX family ubiquitin ligases (DTX1 to DTX4 and DTX3L) are characterized by a RING domain followed by a C-terminal domain (DTC) of hitherto unknown function. Here, we use two label-free mass spectrometry techniques to investigate the interactome and ubiquitinated substrates of human DTX2 and identify a large proportion of proteins associated with the DNA damage repair pathway. We show that DTX2-catalyzed ubiquitination of these interacting proteins requires PARP1/2-mediated ADP-ribosylation and depends on the DTC domain. Using a combination of structural, biochemical, and cell-based techniques, we show that the DTX2 DTC domain harbors an ADP-ribose-binding pocket and recruits poly-ADP-ribose (PAR)-modified proteins for ubiquitination. This PAR-binding property of DTC domain is conserved across the DELTEX family E3s. These findings uncover a new ADP-ribose-binding domain that facilitates PAR-dependent ubiquitination.
    DOI:  https://doi.org/10.1126/sciadv.abc0629
  5. Mol Med Rep. 2020 Aug 19.
    Li X, Ren G, Cai C, Yang X, Nie L, Jing X, Li C.
      Periodontitis is a chronic infectious disease that alters the cellular microenvironment and promotes bone absorption. Bone morphogenetic protein 9 (BMP9) serves an important role in proliferation and differentiation, and tumor necrosis factor‑alpha (TNF‑α) is an important contributor to bone resorption. The present study aimed to investigate the effect of osteogenic differentiation in the presence of BMP9 and TNF‑α in rat follicle stem cells (rDFCs). rDFCs were transfected with adenoviruses expressing BMP9 (AdBMP9) and the expression levels of important proteins [BMP9, β‑catenin, glycogen synthase kinase 3β (GSK3β), phosphorylated‑GSK3β, calcium/calmodulin dependent protein kinase II and nemo like kinase] were determined using western blotting. The effect of osteogenesis was analyzed using reverse transcription‑quantitative PCR, in addition to alkaline phosphatase, Alizarin Red S, and hematoxylin and eosin staining methods. The results of the present study revealed that TNF‑α activated the canonical Wnt signaling pathway and suppressed osteogenesis. High concentrations of Dickkopf 1 (DKK1) reduced the osteogenic differentiation of AdBMP9‑transduced rDFCs, whereas low concentrations of DKK1 promoted BMP9‑induced bone formation, which was discovered to partially act via the canonical and non‑canonical Wnt signaling pathways. In conclusion, the findings of the present study suggested that the enhanced promoting effect of BMP9 alongside the treatment with low concentrations of DKK1 may be useful for treating periodontitis bone absorption.
    DOI:  https://doi.org/10.3892/mmr.2020.11439
  6. Anal Biochem. 2020 Sep 11. pii: S0003-2697(20)30432-2. [Epub ahead of print] 113900
    Chen Y.
      Extracellular pH plays vital roles in physiological and pathological processes including tumor metastasis and chemotherapy resistance. Abnormal extracellular pH is known to be associated with various pathological states, such as those in tumors, ischemic stroke, infection, and inflammation. Specifically, dysregulated pH is regarded as a hallmark of cancer because enhanced glycolysis and poor perfusion in most solid malignant tumors create an acidic extracellular environment, which enhances tumor growth, invasion, and metastasis. Close connection between the cell functions with extracellular pH means that precise and real-time measurement of the dynamic change of extracellular pH can provide critical information for not only studying physiological and pathological processes but also diagnosis of cancer and other diseases. This review highlights the recent development of based fluorescent probes for extracellular pH measurement, including design strategies, reaction mechanism and applications for the detection and imaging of extracellular pH.
    Keywords:  bioimaging; detection; extracellular pH; fluorescence probe
    DOI:  https://doi.org/10.1016/j.ab.2020.113900