Chloroplastic protein prenylation: an internal or external affair? Reconciling biochemical data through a new hypothesis.

Protein prenylation facilitates membrane association, protein interactions, and trafficking by attaching isoprenoid groups to C-terminal cysteine residues in the cytosol, with subsequent proteolysis and carboxymethylation occurring in the endoplasmic reticulum. In contrast this classic pathway, an organelle-autonomous prenylation pathway in plastids has long been hypothesized, however, its biochemical mechanisms remain unconfirmed. This review synthesizes multi-omics and genetic evidence to propose that plastid prenylation likely involves nuclear-encoded proteins modified in the cytosol, with final processing at the chloroplast envelope rather than the endoplasmic reticulum. In addition, the processing of prenylated chloroplast protein precursors may be integrated into the protein targeting machinery. By challenging the notion of fully chloroplast-independent prenylation, this hypothesis and theory article offers new insights into organellar protein modification in eukaryotes.