ZBP1 and heatstroke

Abstract

Heatstroke, which is associated with circulatory failure and multiple organ dysfunction, is a heat stress-induced life-threatening condition characterized by a raised core body temperature and central nervous system dysfunction. As global warming continues to worsen, heatstroke is expected to become the leading cause of death globally. Despite the severity of this condition, the detailed mechanisms that underlie the pathogenesis of heatstroke still remain largely unknown. Z-DNA-binding protein 1 (ZBP1), also referred to as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, was initially identified as a tumor-associated and interferon (IFN)-inducible protein, but has recently been reported to be a Z-nucleic acid sensor that regulates cell death and inflammation; however, its biological function is not yet fully understood. In the present study, a brief review of the main regulators is presented, in which the Z-nucleic acid sensor ZBP1 was identified to be a significant factor in regulating the pathological characteristics of heatstroke through ZBP1-dependent signaling. Thus, the lethal mechanism of heatstroke is revealed, in addition to a second function of ZBP1 other than as a nucleic acid sensor.

Keywords: RIPK3; ZBP1; heatstroke; necroptosis; programmed cell death.

Figure 1

Schematic representation of full-length ZBP1. ZBP1 encodes two N-terminal Z-DNA-binding domains, which are reported to bind to Z-DNA, B-DNA, and RNA. ZBP1 also has two receptor-interacting protein homotypic interaction motif (RHIM) domains in the central part that facilitate the interaction with other RHIM domain-containing proteins. These RHIM domains are important in mediating ZBP1-dependent cell death and inflammatory responses (13, 14).

Figure 2

ZBP1 senses RNA virus infection, DNA virus infection, and heat stress, following which the necrotic complex will be assembled to induce apoptosis, pyroptosis, and necroptosis (14, 16).

Figure 3

Possible pathophysiological pathway leading to heatstroke. The sequence of events leading to heatstroke involves a transition from a compensable thermoregulatory state to the non-compensable condition. Heat stress initiates a thermoregulatory response to maintain the balance of heat production and heat dissipation. When the arterial blood pressure begins to decrease substantially, the core temperature begins to increase rapidly and becomes non-compensable. This thermoregulatory failure aggravates pathophysiological processes, including the inflammatory response and multi-organ dysfunction, and is ultimately expressed as heatstroke (3).

Figure 4

Schematic of the mechanism of heat stress-induced programmed cell death, disseminated intravascular coagulation (DIC), and multiple organ dysfunction syndrome (MODS) (14, 16).