Keratin 17 modulates hair follicle cycling in a TNFα-dependent fashion

Abstract

Mammalian hair follicles cycle between stages of rapid growth (anagen) and metabolic quiescence (telogen) throughout life. Transition from anagen to telogen involves an intermediate stage, catagen, consisting of a swift, apoptosis-driven involution of the lower half of the follicle. How catagen is coordinated, and spares the progenitor cells needed for anagen re-entry, is poorly understood. Keratin 17 (K17)-null mice develop alopecia in the first week post-birth, correlating with hair shaft fragility and untimely apoptosis in the hair bulb. Here we show that this abnormal apoptosis reflects premature entry into catagen. Of the proapoptotic challenges tested, K17-null skin keratinocytes in primary culture are selectively more sensitive to TNF␣. K17 interacts with TNF receptor 1 (TNFR1)-associated death domain protein (TRADD), a death adaptor essential for TNFR1-dependent signal relay, suggesting a functional link between this keratin and TNF␣ signaling. The activity of NF-B, a downstream target of TNF␣, is increased in K17-null skin. We also find that TNF␣ is required for a timely anagen-catagen transition in mouse pelage follicles, and that its ablation partially rescues the hair cycling defect of K17-null mice. These findings identify K17 and TNF␣ as two novel and interdependent regulators of hair cycling.[Keywords: Intermediate filament; hair cycle; apoptosis; anagen; catagen] Supplemental material is available at http://www.genesdev.org.

Introducing intermediate filaments: from discovery to disease

“…In particular, K8/K18 filaments have been described to protect liver hepatocytes during apoptosis-promoting stress conditions, either by regulating the targeting of death receptors at the cell surface (120) or by controlling the formation of the death-inducing signaling complex (DISC) through protein sequestration and thereby controlling downstream signaling (113)(114)(115). A similar regulatory role based on the sequestration of DISC components has been suggested for hair follicle K17 in the modulation of TNF-α signaling (116). The importance of IFs has been also observed downstream in death receptor pathways, since keratins have been suggested to form platforms for caspase activation, to limit the intracellular distribution of active caspases (117), and to regulate the ability of death receptor-associated proteins to activate survival-related signaling pathways (118).…”

The TFIID subunit TAF4 regulates keratinocyte proliferation and has cell-autonomous and non-cell-autonomous tumour suppressor activity in mouse epidermis

“…Similarly, upregulation K16, also implicated in promoting the anagen phase (Tong and Coulombe, 2006), and of several KAPs normally transcribed during anagen, is observed. Two further observations might be directly relevant to the hair cycling defects.…”

Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18

“…fragil., epidermal fragility; Unalt., unaltered; suprab., suprabasal; q, an increase; +, present; 2, absent. Data were compiled from knockout mice for Krt1 (this manuscript); Krt10 (Reichelt et al, 2001), Krt1/Krt10 (Wallace et al, 2012), Krt 17 (McGowan et al, 2002;Tong and Coulombe, 2006). The MouseWG-6v2.0 Expression BeadChip kit (Illumina, Inc., San Diego, CA, USA) was used to probe triplicate Krt1 +/+ and Krt1 2/2 samples.…”