LIR-dependent LMX1A/LMX1B autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience

Abstract

The LIM homeodomain transcription factors LMX1A and LMX1B are essential mediators of midbrain dopaminergic neuronal (mDAN) differentiation and survival. Here we show that LMX1A and LMX1B are autophagy transcription factors in iPSC-derived human mDANs, each contributing to the expression of important autophagy genes including ULK1, ATG7, ATG16L1 and TFEB. Suppression of LMX1A and LMX1B in mDANs reduces basal autophagy, lowers mitochondrial respiration, and elevates mitochondrial ROS levels; meanwhile overexpression protects against rotenone poisoning in mDANs in vitro. Significantly, we show that LMX1A and LMX1B bind to multiple ATG8 proteins via LIR-type interactions, in a manner dependent on subcellular localisation and nutrient status: LMX1B interacts with LC3B in the nucleus under basal conditions via a C-terminal LIR, but binds to cytosolic LC3B and is degraded by autophagy during nutrient starvation, and LIR mutant LMX1B is unable to protect mDANs against rotenone. This establishes an LMX1A/LMX1B-autophagy regulatory nexus that helps explain the protective roles of these transcription factors in the adult midbrain, thus having implications for our understanding of mDAN decline in PD.

Dynamic protein-protein interactions of the potato autophagy-related StATG8 family proteins, which are also associated with WRKY transcription factor and pathogen effector in the nucleus

“…Although initially proposed as a nuclear-cytoplasmic shuttle responsible for removing proteins from the nucleus, recent reports have suggested a broader functional repertoire [21,25]. ATG8 has been identi ed as a transcriptional cofactor that participates in the regulation of gene expression together with transcriptional regulators [23,24]. In particular, in plants, MeWRKY and MeATG8 interact to activate PR gene transcription [26].…”

“…Of course, under the absence of stress conditions, some autophagic bodies were observed. StATG8 interacts with the transcription factor WRKY Previous studies have shown that WRKY, a transcriptional regulator, interacts with ATG8, and it has recently been reported that human LC3B interacts with the transcription factor LMX1B and acts as a transcriptional cofactor [23,24]. Based on this, putative candidates with AIM among Arabidopsis transcription factors were analyzed in the iLIR Autophagy Database.…”

“…Recently, the function of a cofactor that binds to transcription regulators and aids in transcription has been unveiled. Nuclear LC3B binds to the LIM homeodomain transcription factor LMX1B and facilitates LMX1B in the transcription of autophagy genes, thereby enhancing stress protection [23,24].…”

Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

“…In post-mitotic mDAn, Lmx1a/b directly regulates the expression of the dopamine transporter (DAT) and the vesicular monoamine transporter 2 (Vmat2), genes necessary for mDAn terminal differentiation and markers of mature mDAn [15][16][17]. According to recent findings, Lmx1a/b expression is also maintained throughout adulthood, and, by regulating autophagy and mitochondrial metabolism, provides protection against cellular stress [18,19]. For all these reasons, Lmx1a is effectively used in combination with other TFs to improve DA differentiation in vitro and in vivo from different cellular systems [15,[20][21][22][23].…”