The IRE1α/XBP1-mediated upregulation of LMTK2 attenuates endoplasmic reticulum stress by enhancing autophagic activity

Lemur tyrosine kinase 2 (LMTK2), a transmembrane protein, is not well characterized regarding its biological functions and regulatory mechanisms. Herein, we demonstrate that LMTK2 functions as an ER stress-induced protein that plays a crucial role in regulating ER stress and safeguarding cells through autophagy pathway. Our study reveals that ER stressors thapsigargin (Tg) and tunicamycin (Tm) upregulate LMTK2 expression via IRE1α-XBP1s signaling in colon cancer cells. LMTK2 overexpression ameliorates Tm-induced ER stress, whereas its knockdown did the opposite. LMTK2 depletion impairs Tg-induced autophagy. The protective effect of LMTK2 against ER stress is autophagy-dependent, evidenced by LMTK2's inability to mitigate ER stress when autophagy was pharmacologically inhibited. These findings establish that LMTK2-mediated ER stress alleviation is dependent on its facilitation of autophagic processes. Importantly, LMTK2 demonstrates a protective role against ER stress-induced apoptosis that is abolished upon autophagy inhibition. Xenograft experiments reveal that LMTK2-deficient tumors exhibited increased apoptotic cells, elevated GRP78 expression, and reduced LC3 levels. Analyses of clinical colon cancer specimens indicate that LMTK2 expression levels correlate with tumor grades and poor patients' survival. These results provide compelling evidence that LMTK2 functions as an ER stress-responsive protein that maintains ER homeostasis and promotes cell survival via autophagy-dependent mechanisms.