The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRER

Cell. 2019 Nov 27;179(6):1306-1318.e18. doi: 10.1016/j.cell.2019.10.018. Epub 2019 Nov 21.


Cells have evolved complex mechanisms to maintain protein homeostasis, such as the UPRER, which are strongly associated with several diseases and the aging process. We performed a whole-genome CRISPR-based knockout (KO) screen to identify genes important for cells to survive ER-based protein misfolding stress. We identified the cell-surface hyaluronidase (HAase), Transmembrane Protein 2 (TMEM2), as a potent modulator of ER stress resistance. The breakdown of the glycosaminoglycan, hyaluronan (HA), by TMEM2 within the extracellular matrix (ECM) altered ER stress resistance independent of canonical UPRER pathways but dependent upon the cell-surface receptor, CD44, a putative HA receptor, and the MAPK cell-signaling components, ERK and p38. Last, and most surprisingly, ectopic expression of human TMEM2 in C. elegans protected animals from ER stress and increased both longevity and pathogen resistance independent of canonical UPRER activation but dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.

Keywords: CRISPR-Cas9; MAPK signaling; aging; endoplasmic reticulum; extracellular matrix; glucosaminoglycan; immune response; stress response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caenorhabditis elegans / immunology
  • Caenorhabditis elegans / physiology*
  • Cell Line
  • Cell Proliferation
  • Disease Resistance
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress
  • Fibroblasts / metabolism
  • Humans
  • Hyaluronoglucosaminidase / metabolism*
  • Immunity, Innate
  • Longevity / physiology*
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Molecular Weight
  • Signal Transduction
  • Unfolded Protein Response*


  • CEMIP2 protein, human
  • Membrane Proteins
  • Hyaluronoglucosaminidase