The CC domain-dependent homodimerization of MLA has been suggested to attract particular WRKY hetero or homo-oligomers for the purpose of downstream signaling. Whether the heterodimer of the CC/TIR domain is therefore also a critical player in downstream signaling remains an open question. However, the coexpression of the CC domains of both Pikh-1 and Pikh-2 was insufficient to induce HR, suggesting that the association of the two CC domains may be related to the formation of AvrPikh-Pikh1-Pikh2 recognition complexes rather than specifically related to a downstream signaling event. The sub-cellular localization of R proteins is relevant to their activity in resistance signalling. The tobacco R gene product N, which confers resistance against tobacco mosaic virus, is found in both the cytoplasm and the nucleus. During TMV infection, the shuttling of p50-activated N from the cytoplasm to the nucleus appears to be required for an effective defence response. As a second example, the activity of the A. thaliana SNC1 and RPS4 have also been associated with their nuclear accumulation. Strikingly, a recent study has confirmed that the enhanced defense responses mounted under conditions of ABA deficiency and high temperature is dependent on the nuclear localization of SNC1 and RPS4. In contrast, the regulation of the potato CC-NBS-LRR Rx protein requires its nucleocytoplasmic distribution, which is brought about by its CC and LRR domains and facilitated by an accessory protein. While the nuclear Rx protein may play a role in transcriptional reprogramming, the cytoplasmic form mounts a defence process against the virus. With respect to the Pik-h product, the Pikh-1 CC domain disrupted its balanced nucleocytoplasmic partitioning through its interaction with both AvrPik-h and Pikh-2. When GFP fusion proteins comprising either the full-length Pikh-1 or specific Pikh-1 domains were expressed in rice protoplasts, it was only the former which retained a balanced distribution between the cytoplasm and the nucleus. Thus, similar to the situation with Rx, the Pikh-1 CC and LRR domains may well have contrasting roles in determining the cellular distribution of the full-length Pikh-1 protein. Given that the full-length Pikh-1 protein was required for HR induction, and that it interacted with AvrPik-h or Pikh-2 in both nucleus and cytoplasm, the assumption is that Pikh-mediated resistance relies on its balanced cellular distribution. Indeed, the enforced restriction of Pikh-1 to either the nucleus or the cytoplasm blocked the AvrPikh-dependent cell death. The full-length and CC domain of Pikh-2 accumulated mostly, and the NBS and LRR domains exclusively, in the nucleus. An enhanced nuclear or cytoplasmic accumulation of Pikh-2 also compromised its HR activity. The inference is that in the expression of Pik-h resistance, Pikh-2 may interact with Pikh-1 in the nucleus to direct transcriptional reprogramming.