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SUMMARY:Salicylic acid and its binding proteins at the crossroads of plant
  and human health - Dan Klessig\, Cornell University
DTSTART:20170427T120000Z
DTEND:20170427T130000Z
UID:TALK72089@talks.cam.ac.uk
CONTACT:38889
DESCRIPTION:Since our discovery in 1990 that SA regulates plant immunity\,
  we have attempted to determine its mechanisms of action in plant immunity
  and other biological processes using genetic\, molecular\, and biochemica
 l approaches. Over two dozen plant SA-binding proteins (SABPs) have been i
 dentified primarily through biochemical methods\, including three high-thr
 oughput screens (Manohar et al.\, 2015\; also see http://bioinfo.bti.corne
 ll.edu/SA2010/). SA binding alters the biochemical and/or biological activ
 ities of these proteins\, generally by inhibit them. We have extended this
  work 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 pha
 rmacological activities of aspirin. Two novel targets of SA/aspirin have b
 een identified across the animal and plant kingdoms. Together the two huma
 n SABPs are associated with most of the major human diseases\, including h
 eart attack\, stroke\, sepsis\, rheumatoid arthritis\, inflammation-associ
 ated cancers\, hepatitis\, and neurodegenerative diseases. One of the iden
 tified human SABPs is High Mobility Group Box1 (HMGB1). In addition to its
  nuclear role in condensing DNA and regulating gene expression\, extracell
 ular HMGB1 is a damage-associated molecular pattern (DAMP)\, which activat
 es immune and inflammatory responses. SA suppresses both the chemo-attract
 ant activity of HMGB1 and the increased expression of pro-inflammatory cyt
 okine and COX-2 genes induced by HMGB1 (Choi et al.\, 2015a). A synthetic 
 SA derivative acetyl 3-aminoethyl SA and natural derivative from the Chine
 se medicinal herb Glycyrrhiza foetida (licorice) amorfrutin B1 have been i
 dentified\, which are much more potent inhibitors than SA of the pro-infla
 mmatory activities of HMGB1. Interestingly\, our parallel study of the pla
 nt ortholog AtHMGB3 revealed that it also functions as a DAMP to activate 
 plant immunity. Moreover\, it binds SA\, which inhibits its immune-inducin
 g activity (Choi et al.\, 2016). The second novel target in humans is Glyc
 eraldehyde 3-Phosphate Dehydrogenase (GAPDH). In addition to its central r
 ole in glycolysis\, human GAPDH participates in several pathological proce
 sses including neuronal cell death associated with Alzheimer's\, Parkinson
 's\, and Huntington's diseases. We discovered that SA\, like the anti-Park
 inson’s drug deprenyl\, suppresses nuclear translocation of GAPDH\, an e
 arly step in cell death\, as well as cell death induced by the DNA alkylat
 ing agent N-methyl-N-nitroso-N1-nitroguanidine (Choi et al.\, 2015b). Acet
 yl 3-aminoethyl SA and amorfrutin B1 not only more tightly bind to GAPDH\,
  but also more effectively suppress nuclear translocation of GAPDH and cel
 l death than SA. In addition to GAPDH’s role in neuronal cell death\, so
 me animal and plant viruses\, such as human Hepatitis A\, B\, C Viruses an
 d Tomato Bushy Stunt Virus (TBSV)\, usurp this host protein for their repl
 ication. We discovered that SA binding to GAPDH inhibits its interaction w
 ith the TBSV minus RNA strand\, thereby suppressing viral replication. Thi
 s finding reveals a novel mechanism of SA action in defense against viral 
 pathogens (Tian et al.\, 2015).\n\nIn summary\, these studies demonstrate 
 that SA can modulate both plant and human health via shared SABPs. Further
 more\, the identification of human HMGB1 and GAPDH as pharmacological targ
 ets of SA/aspirin provides new insights into the mechanisms of action of o
 ne of the world’s longest and most used natural and synthetic drug. It m
 ay also provide an explanation for the protective effects of low-dose aspi
 rin usage. Moreover\, the identification of natural and synthetic SA deriv
 atives with greater potency for inhibition of HMGB1 and GAPDH provides pro
 of-of-concept that new SA-based compounds with high efficacy are attainabl
 e ( Klessig et al.\, 2016).
LOCATION:Department of Plant Sciences\, Large Lecture Theatre
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