Salicylic acid and its binding proteins at the crossroads of plant and human health

During the past several years, we have identified over two dozen plant SA-binding proteins (SABPs), primarily through biochemical methods including three high-throughput screens. SA binding alters the biochemical and/or biological activities of these proteins.

This work has been extended to humans, since the most widely used medicine aspirin (acetyl SA) is rapidly converted to SA after ingestion and SA has most of the same pharmacological activities of aspirin. Two novel targets of SA/aspirin have been identified across the animal and plant kingdoms. Together the two human SABPs are associated with most of the major human diseases, including heart attack, arthritis, cancers, and Alzheimer’s and Parkinson’s diseases.

One of the identified human SABPs is nuclear High Mobility Group Box1 (HMGB1). Extracellular HMGB1 is a damage-associated molecular pattern (DAMP), which activates immune and inflammatory responses. SA suppresses HMGB’s pro-inflammatory activities. A parallel study of the plant ortholog AtHMGB3 revealed that it also functions as a DAMP to activate plant immunity, which is inhibited by SA.

The second novel target in is Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH). In addition to its central role in glycolysis, GAPDH participates in several pathological processes including cell death associated with neurodegenerative diseases. SA suppresses this cell death. Some animal and plant viruses, such as human Hepatitis A, B, C Viruses and Tomato Bushy Stunt Virus (TBSV), usurp this host protein for their replication. SA binding to GAPDH inhibits TBSV replication. Synthetic and natural SA derivatives have been identified, which are 10-70 times more potent than SA at inhibiting HMGB1’s and GAPDH’s disease-associated activities, thereby providing proof-of-concept that better SA-based drugs can be obtained.

Dr. Daniel Klessig

Boyce Thompson Institute, Cornell University

Dr. Klessig’s early research career, which started as a graduate student with Nobel Laureate James Watson, focused on the molecular biology of human adenovirus. His studies of this DNA tumor virus resulted in a molecular explanation for the failure of pharmaceutical companies to produce adenovirus vaccines in monkey cells in the 1950s.

This work also provided some of the first evidence for split genes and led him to propose in 1977 that mRNAs in animals are produced by a process of RNA splicing (intra-molecular ligation). Richard Roberts, with whom Dr Klessig worked, and Phillip Sharp were awarded the Nobel Prize in Physiology and Medicine in 1993 for the discovery of split genes and RNA splicing. While continuing to study adenoviruses until 1996, he initiated a research program in plant molecular biology in the early 1980’s. The goal of his ongoing research is to understand how plants protect themselves against microbial pathogens.

Over the past decades he and his research team identified components in pathways, which enable plants to recognize that they are being attacked in order for them to rapidly mount defenses against the invader. Their efforts resulted in the identification of two critical defense-signaling molecules in plants – salicylic acid (SA) and nitric oxide (NO). Interestingly, both SA and NO also play roles in human health. NO is a potent endogenous signaling molecule in human, where it plays critical roles in inflammatory and immune responses, in neural transmission, and in muscle physiology. Dr Klessig’s work demonstrated that several critical players of animal NO signaling are also operative in plants during their response to pathogen assault. In 1990s Klessig and coworkers discovered the importance of SA in plants by demonstrating that it is a hormone produced by plants to activate their immune systems. Their subsequent studies identified the first mobile signal for systemic acquired resistance, which is a state of heightened defense that is activated throughout a plant after an initial infection. This signal is methyl salicylate, a modified and inactive form of SA. Their research also revealed that, in contrast to most hormones in plants and animals, SA acts through many different protein targets to mediate its many effects on immunity and other plant processes.

 Interestingly, derivatives of SA, including aspirin (acetyl SA), have been used by humans for thousands of years to treat a variety of maladies. The prevailing view in the biomedical community has been that aspirin, the most widely use drug worldwide for over a century, works primarily, if not exclusively, by irreversibly inhibiting the enzymatic activities of cyclooxygenases 1 and 2 (COX1 and COX2), However, aspirin is rapidly converted in the body to SA, which has similar pharmacological effects as aspirin, despite its poor ability to inhibit the cyclooxygenases. Klessig's recent studies are addressing this conundrum by revealing several novel targets through which SA mediates its many pharmacological effects. These targets include Glyceraldehyde 3-Dehydrogenase (GAPDH) and High Mobility Group Box1 (HMGB1). HMGB1, when released outside of cells following tissue injury or secretion by certain immune or cancer cells, has potent pro-inflammatory activities associated with rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, lupus, sepsis, inflammation-associated cancers such as colorectal and mesothelioma cancers, and Alzheimer's disease. GAPDH facilitates infection by the hepatitis viruses and is a major suspect in the neurodegenerative diseases Alzheimer’s, Parkinson’s, and Huntington’s. SA binds to both, thereby inhibiting their disease-associated activities. The identification of synthetic and natural derivatives of SA, which are 10-70 times more potent inhibitors of GAPDH's cell death-associated activities and HMGB1's pro-inflammatory activities than SA provides proof-of-concept that better SA-based drugs can be obtained.