Microtubule-associated protein 1S (MAP1S) bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation.
The ubiquitously distributed MAP1S is a homologue of the exclusively neuronal distributed microtubule-associated protein 1A and 1B (MAP1A/B). They give rise to multiple isoforms through similar post-translational modification. Isoforms of MAP1S have been implicated in microtubule dynamics and mitotic abnormalities and mitotic cell death. Here we show that ablation of the Map1s gene in mice caused reduction in the B-cell CLL/lymphoma 2 or xL (Bcl-2/xL) and cyclin-dependent kinase inhibitor 1B (P27) protein levels, accumulation of defective mitochondria, and severe defects in response to nutritive stress, suggesting defects in autophagosomal biogenesis and clearance. Furthermore, MAP1S isoforms interacted with the autophagosome-associated light chain 3 of MAP1A/B (LC3), a homologue of yeast autophagy-related gene 8 (ATG8), and recruited it to stable microtubules in a MAP1S and LC3 isoform-dependent mode. In addition, MAP1S interacted with mitochondrion-associated leucine-rich PPR-motif containing protein (LRPPRC) that interacts with the mitophagy initiator and Parkinson disease-related protein Parkin. The three-way interactions of MAP1S isoforms with LC3 and microtubules as well as the interaction of MAP1S with LRPPRC suggest that MAP1S isoforms may play positive roles in integration of autophagic components with microtubules and mitochondria in both autophagosomal biogenesis and degradation. For the first time, our results clarify roles of MAP1S in bridging microtubules and mitochondria with autophagic and mitophagic initiation, maturation, trafficking, and lysosomal clearance. Defects in the MAP1S-regulated autophagy may impact heart disease, cancers, neurodegenerative diseases, and a wide range of other diseases.
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA.
Rui
R
Xie
Susan
S
Nguyen
Kerstin
K
McKeehan
Fen
F
Wang
Wallace L
WL
McKeehan
Leyuan
L
Liu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071190:Autophagy-Related Protein 8 Family; D057809:HEK293 Cells; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000071190:Autophagy-Related Protein 8 Family; C498698:GABARAPL2 protein, human; C493240:MAP1S protein, human; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms
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