Inflammatory signaling drives SQSTM1-dependent suppression of interferon-γ-induced MHC class I

Tanaka, K.; Yamashita, S.; Shuto, H.; Hirayama, A.; Shimauchi, A.; Utsumi, T.; Ninomiya, T.; Tsubouchi, K.; Otsubo, K.; Shibahara, D.; Iwama, E.; Okamoto, I.

doi:10.64898/2026.10.23.761340

bioRxiv · 10.64898/2026.10.23.761340

Inflammatory signaling drives SQSTM1-dependent suppression of interferon-γ-induced MHC class I

Tanaka, K.·Yamashita, S.·Shuto, H.·Hirayama, A.·Shimauchi, A.·Utsumi, T.·Ninomiya, T.·Tsubouchi, K.·Otsubo, K.·Shibahara, D.·Iwama, E.·Okamoto, I.

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Abstract

An immune-inflamed tumor microenvironment features interferon-{gamma} (IFN-{gamma}) and inflammatory cytokines, yet how cancer cells integrate these opposing signals to regulate immunogenicity remains poorly understood. Here, we investigated the effect of interleukin-1{beta} (IL-1{beta}) on IFN-{gamma}-induced major histocompatibility complex class I (MHC-I) expression in non-small cell lung cancer (NSCLC) cells. IL-1{beta} suppressed IFN-{gamma}-induced surface MHC-I expression despite preserved or enhanced expression of antigen presentation-related genes, indicating post-transcriptional regulation. This effect emerged 12-24 h after stimulation and accompanied accelerated MHC-I turnover without altering total protein abundance. RNA sequencing identified selective induction of autophagy-related genes under combined IFN-{gamma} and IL-1{beta} stimulation. Immunofluorescence and biochemical analyses demonstrated MHC-I redistribution to autophagosome-lysosome compartments. Mechanistically, the selective autophagy receptor SQSTM1 associated with MHC-I and was required for its surface downregulation, whereas NBR1 depletion and autophagy or lysosomal inhibition failed to restore MHC-I expression, indicating a nonredundant role for SQSTM1. These findings identify post-translational MHC-I trafficking as an underappreciated regulatory layer linking inflammatory signaling to the canonical IFN-{gamma}-MHC-I axis and reveal an SQSTM1-dependent mechanism controlling MHC-I surface availability in immune-inflamed tumors.

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Tanaka, K., Yamashita, S., Shuto, H., Hirayama, A., Shimauchi, A., Utsumi, T., Ninomiya, T., Tsubouchi, K., Otsubo, K., Shibahara, D., Iwama, E., Okamoto, I.. 2026-10-27. Inflammatory signaling drives SQSTM1-dependent suppression of interferon-γ-induced MHC class I. https://doi.org/10.64898/2026.10.23.761340

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