bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2023‒05‒07
three papers selected by
Su Hyun Lee
Harvard University

  1. EMBO J. 2023 May 04. e112712
      cGAS-STING signalling is induced by detection of foreign or mislocalised host double-stranded (ds)DNA within the cytosol. STING acts as the major signalling hub, where it controls production of type I interferons and inflammatory cytokines. Basally, STING resides on the ER membrane. Following activation STING traffics to the Golgi to initiate downstream signalling and subsequently to endolysosomal compartments for degradation and termination of signalling. While STING is known to be degraded within lysosomes, the mechanisms controlling its delivery remain poorly defined. Here we utilised a proteomics-based approach to assess phosphorylation changes in primary murine macrophages following STING activation. This identified numerous phosphorylation events in proteins involved in intracellular and vesicular transport. We utilised high-temporal microscopy to track STING vesicular transport in live macrophages. We subsequently identified that the endosomal complexes required for transport (ESCRT) pathway detects ubiquitinated STING on vesicles, which facilitates the degradation of STING in murine macrophages. Disruption of ESCRT functionality greatly enhanced STING signalling and cytokine production, thus characterising a mechanism controlling effective termination of STING signalling.
    Keywords:  ESCRT; cGAS-STING; innate immunity; lysosomal degradation; vesicular trafficking
  2. Nat Cell Biol. 2023 May 04.
      Stimulator of interferon genes (STING) orchestrates the production of proinflammatory cytokines in response to cytosolic double-stranded DNA; however, the pathophysiological significance and molecular mechanism underlying the folding and maturation of nascent STING protein at the endoplasmic reticulum (ER) remain unknown. Here we report that the SEL1L-HRD1 protein complex-the most conserved branch of ER-associated degradation (ERAD)-is a negative regulator of the STING innate immunity by ubiquitinating and targeting nascent STING protein for proteasomal degradation in the basal state. SEL1L or HRD1 deficiency in macrophages specifically amplifies STING signalling and immunity against viral infection and tumour growth. Mechanistically, nascent STING protein is a bona fide substrate of SEL1L-HRD1 in the basal state, uncoupled from ER stress or its sensor inositol-requiring enzyme 1α. Hence, our study not only establishes a key role of SEL1L-HRD1 ERAD in innate immunity by limiting the size of the activable STING pool, but identifies a regulatory mechanism and therapeutic approach to targeting STING.
  3. Trends Cell Biol. 2023 Apr 27. pii: S0962-8924(23)00071-5. [Epub ahead of print]
      The covalent attachment of ubiquitin is a common regulatory mechanism in various proteins. Although it has long been thought that the substrates of ubiquitination are limited to proteins, recent studies have changed this view: ubiquitin can be conjugated to lipids, sugars, and nucleotides. Ubiquitin is linked to these substrates by the action of different classes of ubiquitin ligases that have distinct catalytic mechanisms. Ubiquitination of non-protein substrates likely serves as a signal for the recruitment of other proteins to bring about specific effects. These discoveries have expanded the concept of ubiquitination and have advanced our insight into the biology and chemistry of this well-established modification process. In this review we describe the molecular mechanisms and roles of non-protein ubiquitination and discuss the current limitations.
    Keywords:  non-canonical ubiquitination; phospholipids; ubiquitin; ubiquitin-like proteins