Within plant cell walls, plasmodesmal channels harbour unique collections of proteins to maintain their structure and facilitate dynamic regulation of cell-to-cell connectivity. Proteomic surveys, combined with evidence from confocal microscopy, have identified heavy metal-associated (HMA) domain-containing proteins as residents at plasmodesmata; however, the functional relevance of this localization is currently unknown. Although HMA domains themselves are present in all kingdoms of life, in plants they can be found in three main families: HPPs, HIPPs, and P1B-type ATPases. Within the last decade, HPPs and HIPPs have emerged as frequent host targets of pathogen-derived molecules, including secreted effectors from bacteria, fungi, and oomycetes, and a viral movement protein. The seemingly conserved targeting of HMA domains throughout distantly related pathosystems suggests that these proteins could play integral roles in plant immunity. This is corroborated by observations of HMA-like domains being integrated into plant immune receptors, enabling direct binding of effectors to activate downstream signalling, as well as genetic evidence highlighting the influence of HPPs and HIPPs on disease susceptibility. Drawing especially from plant pathology studies, we speculate about the potential metallochaperone and signalling functions of these enigmatic plasmodesmal components.
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