l‐lysine metabolism to N‐hydroxypipecolic acid: an integral immune‐activating pathway in plants

Abstract

l-lysine catabolic routes in plants include the saccharopine pathway to α-aminoadipate and decarboxylation of lysine to cadaverine. The current review will cover a third l-lysine metabolic pathway having a major role in plant systemic acquired resistance (SAR) to pathogen infection that was recently discovered in Arabidopsis thaliana. In this pathway, the aminotransferase AGD2-like defense response protein (ALD1) α-transaminates l-lysine and generates cyclic dehydropipecolic (DP) intermediates that are subsequently reduced to pipecolic acid (Pip) by the reductase SAR-deficient 4 (SARD4). l-pipecolic acid, which occurs ubiquitously in the plant kingdom, is further N-hydroxylated to the systemic acquired resistance (SAR)-activating metabolite N-hydroxypipecolic acid (NHP) by flavin-dependent monooxygenase1 (FMO1). N-hydroxypipecolic acid induces the expression of a set of major plant immune genes to enhance defense readiness, amplifies resistance responses, acts synergistically with the defense hormone salicylic acid, promotes the hypersensitive cell death response and primes plants for effective immune mobilization in cases of future pathogen challenge. This pathogen-inducible NHP biosynthetic pathway is activated at the transcriptional level and involves feedback amplification. Apart from FMO1, some cytochrome P450 monooxygenases involved in secondary metabolism catalyze N-hydroxylation reactions in plants. In specific taxa, pipecolic acid might also serve as a precursor in the biosynthesis of specialized natural products, leading to C-hydroxylated and otherwise modified piperidine derivatives, including indolizidine alkaloids. Finally, we show that NHP is glycosylated in Arabidopsis to form a hexose-conjugate, and then discuss open questions in Pip/NHP-related research.

The Arabidopsis thaliana N‐recognin E3 ligase PROTEOLYSIS1 influences the immune response

“…Increased SARD4 protein levels in prt1‐1 were not accompanied by changed SARD4 transcript accumulation, nor by accumulation of AGD2‐like defense response protein1 ( ALD1 ), the other enzyme involved in Pip biosynthesis from L‐lysine (Hartmann et al, ) (Figure c), which may indicate that they are subject to post‐translational regulation. Recently, it was demonstrated that Pip biosynthesis is tightly regulated by EDS1/PAD4 signaling (Hartmann & Zeier, ; Hartmann et al, ). Increased abundance of EDS1 (and several EDS1‐responsive proteins) in untreated prt1‐1 plants was accompanied by small changes in the accumulation of EDS1‐responsive transcripts, including FLAVIN‐DEPENDENT MONOOXYGENASE 1 ( FMO1 ), a key component of plant immunity (Bartsch et al, 2006; Koch et al, 2006; Mishina and Zeier, 2006) that catalyzes the hydroxylation of Pip, CALMODULIN‐BINDING PROTEIN 60‐LIKEg ( CBP60g ) and ISOCHORISMATE SYNTHASE1 ( ICS1 ) (Cui et al, ) (Figure c).…”

A holistic view on plant effector-triggered immunity presented as an iceberg model

“…Now, the SARD1 and to a lesser extent also the CBP60g transcripts themselves are upregulated by SA in an NPR1-and NPR3/4-dependent manner [57], which indicates that SA signaling is self-perpetuating, since SARD1 the overexpression activates immunity [61]. This self-amplification loop also involves NHP, as the biosynthesis genes ALD1 and FMO1 are dependent on SARD1/CBP60g and NPR1/3/4 regulation as well, thereby linking SA and NHP signaling [48,57,60,62,63]. Among the immunity-related genes upregulated in the loop many encode PRRs and NLRs [57], and in particular overexpression of NLRs can on its own stimulated defense responses, which explains how the self-perpetuating loop amplifies immunity.…”

“…The activation of transcriptional reprogramming in CNL-mediated ETI is less clear, but can be speculated to be caused by immune signals spreading from cells that have undergone HR. The hormone network involves an interplay of salicylic acid (SA), jasmonic acid (JA), ethylene (Et), and N-hydroxypipecolic acid (NHP) [16,48]. Many enzymes and other proteins, which are regulated during PTI and ETI, have been identified as being important for immunity due to their association with these hormones.…”

“…The flavin-dependent monooxygenase, FMO1, subsequently hydroxylates pipecolic acid into NHP, which is the active signaling hormone. NHP acts synergistically with SA in stimulating immunity [48]. JA is synthesized in the chloroplast and peroxisome from unsaturated fatty acids primarily via 12-oxo-phytodienoic acid.…”

JMJ14 encoded H3K4 demethylase modulates immune responses by regulating defence gene expression and pipecolic acid levels

“…Pip is hydroxylated to N‐hydroxy‐pipecolic acid (NHP) by FLAVIN‐DEPENDENT MONOOXYGENASE 1 (FMO1) and FMO1 is essential for biologically induced SAR (Mishina & Zeier, ; Chen et al , ; Hartmann et al , ). NHP confers SAR on both ald1 and fmo1 plants (Chen et al , ; Hartmann et al , ), suggesting that NHP acts downstream of Pip (Hartmann & Zeier, ). Relationship between NHP and other SAR inducers remains unknown at present.…”