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32.c: Biochemistry, Climate Change and Human Health

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    Written by John Mahowald, MD, and Henry Jakubowski

    Under Construction 4/1/23


    Climate change affects human health and of course the health of the biosphere to which we are inextricably linked.  We all know that pollution from the use of fossil fuels also has severe health consequences independent of effects mediated more directly by climate change.  A solution to both is to dramatically decrease the use of fossil fuels and mitigate pollution from their use.  People most likely do not understand how climate change and fossil fuel use are linked to human health.  If they did, perhaps they would become advocates for climate change action.  This section will cover how climate change and fossil fuel use affect aspects of human health and diseases.  In this section we will focus on heat-related illness, cardiovascular, pulmonary, and allergic.  Each subsection will begin with a generalized medical description of the health issue, followed by a detailed biochemical description of at least one relevant example.  We'll tackle climate change, emerging disease and pandemics in the next chapter section.

    Heat-Related Illness

    Intro - JM

    Heat illnesses, etc 

    Biochemical Mechanisms - Heatstroke

    The actual biochemical mechanisms of heat stroke effects (circulatory failure, organ injury, uncontrolled clotting, death) are not fully understood.  Certainly, cell death plays a major role, but not through the classical apoptotic pathway which depends on the activation of caspases (see Chapter 28.14).  Rather, cell death occurs through necroptosis, a caspase-independent pathway. In necroptosis, an upstream protein kinase RIPK3 (receptor-interacting serine/threonine protein kinase 1) activates through phosphorylation the effector protein MLKL (mixed lineage kinase domain-like protein).  Phosphorylated-MLKL then translocates to the cell membrane where it leads to calcium influx and plasma membrane damage in the final "execution" phase of cell necrosis.   

    The activation of RIPK3 and MLKL through other receptors, including the toll-like receptors (TLR3 and TLR4), and tumor necrosis factor receptor 1 (TNF-R1), is shown in Figure \(\PageIndex{x}\) below.

    Roles of RIPK3 in necroptosis, cell signaling, and diseaseFig1.svg

    Figure \(\PageIndex{x}\): Activation of RIPK3 by multiple stimuli. Morgan MJ, Kim YS. Roles of RIPK3 in necroptosis, cell signaling, and disease. Exp Mol Med. 2022 Oct;54(10):1695-1704. doi: 10.1038/s12276-022-00868-z. Epub 2022 Oct 12. PMID: 36224345; PMCID: PMC9636380.  Creative Commons Attribution 4.0 International License.

    RIPK3 can be activated via various receptors when bound by their respective ligands. These are TNF receptor 1 (TNF-R1), CD95, death receptors (DR4/5), Toll-like receptors (TLR3/4), and Z-DNA-binding protein-1 (ZBP1)/DAI. In the first three of these pathways (but not TLR3/4 or ZBP1), RIPK1 is required and binds to RIPK3 through its receptor-interacting protein homotypic interaction motif (RHIM). In the case of ZBP1, RIPK3 is recruited directly via the ZBP1 RHIM domain, while in the case of TLR3/4, RIPK3 is recruited indirectly via the RHIM domain of TRIF. Once activated, RIPK3 autophosphorylates and then phosphorylates and activates MLKL to induce a conformational change and translocation to the membrane, where membrane permeabilization follows. During this process, post-translational modifications positively and negatively regulate the necroptosis pathway. Two E3 ligases, Pellino-1 (PELI1) and carboxy terminus of HSC70-interacting protein (CHIP), may control the basal threshold of necroptosis. Another E3 ubiquitin ligase, TRIM21, is proposed to be a regulator of necroptotic cell death in response to TRAIL. PPM1B suppresses necroptosis by dephosphorylating RIPK3.

    The domain structure and phosphorylation sites on human RIPK3 are shown in Figure \(\PageIndex{x}\) below.


    Human RIPK3 C-lobe phosphorylation is essential for necroptotic signalingFig2.svg

    Figure \(\PageIndex{x}\):  Meng, Y., Horne, C.R., Samson, A.L. et al. Human RIPK3 C-lobe phosphorylation is essential for necroptotic signaling. Cell Death Dis 13, 565 (2022).  Creative Commons Attribution 4.0 International License.

    "Schematic of human RIPK3 domain architecture and the phosphorylation sites identified. Phosphorylation sites with proposed functions are shown at the top. pT224 and pS227 positively regulate necroptosis (green) by recruiting MLKL. pS164 and pT165 negatively regulate necroptosis by inhibiting RIPK3 kinase activity (red) [38]. Phosphorylation of T182 (grey) was proposed to promote RIPK3 kinase activity and to recruit PELI1 to mediate proteasomal degradation of RIPK3 [54]. Phosphorylation sites with unknown functions are shown on the bottom (white). Asterisks (*) denotes multiple serine/threonine on the same peptide, as such the exact site of phosphorylation could not be unambiguously identified."

    Figure x shows a complex, the necrosome, containing multiple activated RIPK3s along with RIPK1. Aggregation of RIPK3 occurs through the RHIM (RIP homotypic interaction motifs) domain through the formation of amyloid fibers. The necrosome then phosphorylates MLKL, which forms oligomers and traffics to the membrane.

    Figure x above also shows that an internal sensor protein for viral DNA can also activate RIPK3.  That protein is ZBP1, or Z-DNA-Binding Protein 1, which also binds Z-RNA.  Nuclear Z-RNA can derive from viruses like influenza A, leading to the activation of the same pathway.  Cytokine expression then produces a systemic inflammatory response.   

    In addition to apoptosis and necroptosis, another type of programmed cell death caused by inflammation is called pyroptosis. Usually occurring in bacterial-infected macrophages, pyroptosis leads to the activation of intracellular inflammasomes, which then activate inflammatory cytokines through selective proteolysis by caspases. In pyroptosis, proteins called gasdermins are cleaved by caspases and their N-terminals self-associate in the cell membrane to form pores, from which the inflammatory cytokines IL-1β, and IL-18 are released. 

    A final programmed cell death pathway for virally-infected cells is called PANoptosis, which uses the PANoptosome complex with downstream results not explained by the other three programmed cell death pathways (pyroptosis, apoptosis, and necroptosis)  ZBP-1 leads to the activation of RIPK3, caspase-8 (key in the apoptosis pathway) and the NLRP3 inflammasome.

    ZBP-1 seems to play a key role in heat stroke.  Its concentration increases with heat stress mediated by the heat shock transcription factor 1 (HSF1., which itself is induced by cellular stress.  HSF1 induces a heat shock response which causes increased transcription of chaperones and heat shock proteins (HSPs) such as ZBP-1.   Deletion/inactivation of ZBP-1, RIPK3, or MLKL and caspase 8 decreases heat stroke. The main role of ZBP-1 in cell death from heat stroke arises from the RIPK3/MLKL pathway and to less extent through cross-talk with the classical apoptosis pathway through caspase 8.

    How does ZBP-1 activate cell death during heat stroke without binding to and activating dsDNA or RNA derived from a viral infection?  Does ZBP-1 have an endogenous ligand other than viral Z-RNA or Z-DNA?  Let's first explore the domain structures of some key proteins in the RIPK3 activation pathway.  Figure x above shows three key proteins, RIPK1, TRIFF, and ZBP1 that interact with RIPK3.  Each of these proteins and RIPK3 have a RHIM domain for protein-protein interactions.   Figure \(\PageIndex{x}\) shows the domain structure of our key protein, ZBP-1, the cytosolic Z-DNA/Z-RNA sensor.


    Figure \(\PageIndex{x}\): Domain structure of ZBP-1 ( )  

    The green bars in the N-terminal part of the protein are the Z-DNA binding domain.  These are also called Zα domains.  These regions are the most ordered in the protein, as indicated by the blue in the AlphaFold confidence bar.

    Figure \(\PageIndex{x}\) shows an interactive iCn3D models  of the AlphaFold-predicted model of human Z-DNA-Binding Protein 1 (ZBP1), (Q9H171)

    AlphaFold-predicted model of human Z-DNA-Binding Protein 1 (ZBP1)- (Q9H171.png

    Figure \(\PageIndex{x}\):  AlphaFold-predicted model of human Z-DNA-Binding Protein 1 (ZBP1), (Q9H171).  (Copyright; author via source).  Click the image for a popup or use this external link:

    The spacefill atoms labeled M1 represent the N-terminal methionine of the protein.  The two Z-DNA binding domains follow, are well-ordered, and are shown as blue cartoons.  Much of the protein can't be predicted as it is most likely intrinsically disordered.  Two fairly well-structured motifs, shown in magenta and cyan are the RHIM1 and RHIM2 protein interaction motifs, which can be shown self-associated through their amyloid-like structures.  These motifs allow ZBP1 to bind to other proteins with RHIM motifs and on to cell death through necrosis.  The C-terminal domain appears to be involved in signal transduction type I interferon-mediated by DNA.

    Figure \(\PageIndex{8}\) shows an interactive iCn3D model of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA (3EYI)

    Second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA (3EYI)V3.png

    Figure \(\PageIndex{8a}\):  Second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA (3EYI).  (Copyright; author via source).  Click the image for a popup or use this external link:

    In the absence of viral DNA or RNA, the Zα domain can bind endogenous ligands.  Moreover, it appears that a deficiency in RIPK1 or of the RHIM in RIPK1 also triggers ZBP1 to induce necroptosis and inflammation. and that its Zα domain is required.  If nuclear export was stopped, ZBP1 activates nuclear RIPK3 and then necroptosis.  This suggests that nuclear ZBP1 interacts with endogenous nuclear Z-nucleic acids, probably Z-RNA from retroelements to activate RIPK3-dependent necroptosis and could lead to some forms of chronic inflammation.  

    Here are a series of finding on RIPK3-dependent cell death on heat stress in mouse fibroblasts that show that Z-nucleic acid binding to ZBP1 is not required for heat stress effects:

    • Heat (43°C for 2 hr) induces phosphorylation of RIPK3 and MLKL within 2 hours, and cleavage of pro-caspases and GSDME in 6 hours but none occurred if RIPK3 was deleted.
    • Deletion of ZBP1 but not RIPK1, TRIF, affect heat induce death so so heat stress acts through ZBP1 and RIPK3.  
    • In mice without ZBP1, the effects of heat stress (clotting, inflammation, organ injury, and death) were prevented.
    • Mutations in the RHIM domain, but not the Zα domains (made to prevent Z-nucleic acid binding) or in the C-terminal signaling region (to stop signaling) prevented death from heat stress .  Hence Z-nucleic acid binding is not required but may contribute to cell death from heat stress.
    • Heat stress caused the aggregation of a ZBP1-GFP (green fluorescent protein) fusion protein through the RHIM domains of ZBP-1

    Hence ZBP1 is an innate pathogen sensor and also an initiator of heat-related death in the absence of pathogens.

    Heat Stroke-Induced Epigenetic Changes

    Short of death, heat stroke can also cause long-term health issues.  Increasing global temperatures are forcing people to work at more dangerous temperatures and at night to reduce heat exposure. Data suggests that people who have had a heat-related illness are more susceptible to additional heat exposure health consequences.   This has been noted in exertional heat illnesses. (such as in athletes).    Additional long-term effects on immune regulation have been observed. Epigenetics may play a role in long-term effects such as greater vulnerability to additional heat challenges.  Studies show that a single episode of exceptional heat stroke changes DNA methylation patterns in bone marrow-derived monocytes from mice.  The monocytes become immunosuppressed allowing for increased microbial disease and reduced heat shock responses.  The epigenetic changes are passed onto progeny monocytes which also shows compromised function.  The epigenetic changes persist 30 days or more and we clearly noted in inflammatory cell signaling pathways.  This suggests a mechanism for the reduced tolerance to those with previous heat-related illnesses.

    Cardiovascular Disease

    Intro- JM


    Biochemical Mechanisms: Key Example


    Pulmonary Disease

    Intro - JM


    Biochemical Mechanism: Key Example

    • PM2.5 from fossil fuels on macrophages, lung disease?
    • xx from climate changes

    Allergic Disease



    Biochemical Mechanism: Key Example


    Pediatric Illness



    Biochemical Mechanism: Key Example



    Emerging Diseases

    Intro - HJ


    Biochemical Mechanisms





    This page titled 32.c: Biochemistry, Climate Change and Human Health is shared under a not declared license and was authored, remixed, and/or curated by Henry Jakubowski.

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