Upon pathogen challenge, host cells have to make a life-and-death decision to fend off infection. Recognition of a pathogen effector by a host resistance (R) protein can lead to effector-triggered immunity (ETI), characterized by rapid programmed cell death (PCD) known as the hypersensitive response (HR)1
. The clearly defined boundary of the HR indicates the presence of a mechanism that controls cell death and survival. Despite intense studies of plant mutants defective in controlling the spread of PCD2
, the regulatory mechanism still remains a mystery.
Localized PCD can induce systemic acquired resistance (SAR) through the production of the immune signal, salicylic acid (SA)3
. SA triggers global transcriptional reprogramming and resistance to a broad-spectrum of pathogens. The receptor for SA has been sought after for many years, mainly through biochemical purification of SA-binding proteins4-6
. However, genetic data for these SA-binding proteins, which include a catalase, a chloroplast carbonic anhydrase, and a methyl SA esterase, suggest that none of them functions as a bona fide
SA receptor. In contrast, genetic studies of SA-insensitive mutants have strongly suggested that NPR1, which contains a BTB (bric à brac, tramtrack, broad-complex) domain, an ankryin repeat domain and a nuclear localization sequence, is a potential SA receptor7
. However, the NPR1 protein does not have significant SA binding activity under different test conditions (Supplementary Fig. 2
Instead of direct binding, SA has been shown to control the nuclear translocation of NPR1 through cellular redox changes8
. In the absence of pathogen challenge, NPR1 is retained in the cytoplasm as an oligomer through redox-sensitive intermolecular disulphide bonds. Upon induction, these disulphide bonds are reduced, releasing NPR1 monomers into the nucleus, where NPR1 serves as a cofactor for transcription factors, such as TGAs, to induce defence-related genes. In the absence of a functional NPR1 protein, SA-induced transcriptional reprogramming is almost completely blocked.
The presence of a BTB domain in NPR1 suggests that like other BTB domain-containing proteins, it may interact with Cullin 3 (CUL3) E3 ligase and mediate substrate degradation9
. However, our research led to the surprising finding that the NPR1 protein itself is degraded by the proteasome. While NPR1 is degraded in the nucleus of resting cells to dampen basal expression of defence genes, it is phosphorylated upon immune activation at an IκB-like phosphodegron motif, ubiquitinylated by a CUL3 E3 ligase, and degraded to sustain maximum levels of target gene expression probably through accelerated recycling of the transcription initiation complex10
. Blocking NPR1 degradation by mutating the IκB-like phophodegron in NPR1 or the two CUL3
genes (cul3a cul3b
) in Arabidopsis
led to elevated basal resistance, but insensitivity to SAR induction. Therefore, nuclear accumulation of NPR1 is needed for basal defence gene expression and resistance, while its subsequent turnover is required for establishing SAR.