Abstract
LC3-interacting region (LIR) motifs are essential for recruiting proteins onto autophagosomes, the hallmark of autophagy. We recently explored the relevance of the specific position of the LIRs in RavZ and ATG4B (autophagy-related 4B). RavZ's N-terminal LIRs drive substrate recognition and enzymatic activity, while its C-terminal LIR aids membrane localization. In contrast, ATG4B's C-terminal LIR is indispensable for LC3B (microtubule-associated protein 1 light chain 3B)-phosphatidylethanolamine (PE) delipidation on autophagosomes but not required for cytosolic LC3B priming, which is mediated solely by its catalytic domain (CAD). These findings underscore the structural adaptation of LIRs for context-specific functions. This novel nuanced understanding provides a framework for developing therapeutic tools to modulate autophagy by precisely targeting LIRs or their associated processes, offering potential treatment for diseases like neurodegenerative disorders and infections characterized by autophagy dysregulation.